I

The Effects of Curcuminoids on Musculoskeletal Pain: A Systematic

Review

Thesis submitted in fulfilment of the Master of Clinical Science

The Joanna Briggs Institute

Faculty of Health Sciences

The University of Adelaide

South Australia

Andrew Gaffey

August 2016

II

Table of Contents

List of Tables .......................................................................................................................... VII

List of Figures ......................................................................................................................... VII

Abstract ................................................................................................................................. VIII

Declaration................................................................................................................................ X

Acknowledgements .................................................................................................................. XI

Chapter 1: Introduction ............................................................................................................. 1

1.1 Overview ......................................................................................................................... 1

1.2 Structure of the thesis ..................................................................................................... 3

1.3 Historical context- Curcuminoids and Turmeric .............................................................. 4

1.4 Polyphenols .................................................................................................................... 5

1.4.1 Polyphenols and inflammation ................................................................................. 6

1.4.2 Polyphenols, inflammation and pain ........................................................................ 7

1.5 Curcuminoids- the Polyphenols in Turmeric ................................................................... 8

1.6 Postulated Bioactive effects of Curcuminoids ................................................................. 9

1.7 Bioavailability of Curcuminoids ..................................................................................... 10

1.7.1 Adjuvants ............................................................................................................... 10

1.7.2 Nanoparticle preparations ...................................................................................... 11

1.7.3 Complexation ......................................................................................................... 11

1.7.4 Non-Curcuminoid portion of turmeric extract.......................................................... 11

1.8 Pain and Definitions ...................................................................................................... 12

III

1.9 The Effects of Curcuminoids on Inflammation .............................................................. 14

1.10 Outcome measures relevant to musculoskeletal pain ................................................. 14

1.11 Validated measures of function ................................................................................... 16

1.12 Evidence-based medicine and systematic reviews ..................................................... 19

1.12.1 The Principles of systematic review ..................................................................... 20

1.12.2 Systematic Reviews assist in establishing evidence-based medicine guidelines . 22

1.13 Gap in the literature .................................................................................................... 23

Chapter 2: Systematic Review Methodology .......................................................................... 26

2.1 Review Objective .......................................................................................................... 26

2.2 Criteria for considering studies for this review .............................................................. 26

2.2.1 Types of intervention(s) ......................................................................................... 26

2.2.2 Types of comparator .............................................................................................. 26

2.2.3 Types of outcomes ................................................................................................. 26

2.2.4 Types of studies ..................................................................................................... 27

2.3 Method of the review..................................................................................................... 27

2.3.1 Search strategy ...................................................................................................... 27

2.3.2 Assessment of methodological quality ................................................................... 31

2.3.3 Data extraction ....................................................................................................... 32

2.3.4 Data synthesis ....................................................................................................... 32

Chapter 3: Results .................................................................................................................. 33

3.1 Description of studies.................................................................................................... 33

IV

3.2 Methodological quality .................................................................................................. 33

3.3 Systematic review findings ............................................................................................ 37

3.3.1 Curcuminoids vs placebo ....................................................................................... 37

3.3.2 Curcuminoids versus Placebo: Measurement of Pain Outcomes .......................... 41

3.3.3 Curcumin versus Placebo: Measurement of Function Outcomes .......................... 42

3.3.4 Curcuminoids versus Placebo: Adverse events ..................................................... 43

3.3.5 Curcuminoids versus a Positive/Active control....................................................... 43

3.3.6 Curcumin versus a Positive/Active Control: Measurement of Pain Outcomes ....... 46

3.3.7 Curcuminoids versus a Positive/Active Control: Measurement of Function

Outcomes ....................................................................................................................... 47

3.3.8 Curcuminoids versus a Positive/Active Control: Adverse Events ........................... 48

3.3.9 Herbomineral combinations including curcuminoids versus placebo, mixed or

singular active controls ................................................................................................... 48

3.3.9 Herbomineral combinations including curcuminoids versus placebo, mixed or

singular active controls: Measurement of Pain Outcome ................................................ 54

3.3.10 Herbomineral combinations including curcuminoids versus placebo, mixed or

singular active controls: Measurement of Function Outcome ......................................... 56

3.3.11 Herbomineral combinations including curcuminoids versus placebo, mixed or

singular active controls: Adverse events ......................................................................... 56

Chapter 4: Discussion and Conclusions ................................................................................. 58

4.1 Introduction ................................................................................................................... 58

4.1.2 Structure of the discussion ......................................................................................... 58

V

4.2 Heterogeneity of Included Studies ................................................................................ 59

4.2.1 Characteristic Variation .......................................................................................... 59

4.2.2 Site of musculoskeletal condition and heterogeneity ............................................. 59

4.2.3 Duration of intervention and heterogeneity ............................................................ 59

4.2.4 Dose/frequency or level of intervention .................................................................. 60

4.2.5 Variation of comparator or treatment ..................................................................... 60

4.2.6 Differences in recording outcomes ......................................................................... 61

4.3 Risk of bias in included studies ..................................................................................... 62

4.4 Curcumin or turmeric and use in acute pain states. ...................................................... 63

4.5 Curcuminoid or turmeric use in chronic pain states ...................................................... 64

4.6 VAS/NRS and pain assessment- general ..................................................................... 66

4.7 VAS- statistical significance versus clinical significance ............................................... 66

4.8 Dose/effect and duration of effect ................................................................................. 68

4.9 WOMAC and function assessment ............................................................................... 70

4.10 Safety of Curcuminoids ............................................................................................... 71

4.11 Significance of the findings ......................................................................................... 72

4.12 Limitations of the review ............................................................................................. 72

4.13 Recommendations ...................................................................................................... 75

4.13.1 Recommendations for practice ............................................................................ 75

4.13.2 Recommendations for primary research .............................................................. 76

4.13.3 Future secondary research .................................................................................. 79

VI

4.14 Conclusion .................................................................................................................. 80

References ............................................................................................................................. 82

Appendix I: Critical Appraisal Instrument .............................................................................. 101

Appendix II: Data Extraction Instrument................................................................................ 102

Appendix III: Excluded studies .............................................................................................. 104

Appendix IV: Characteristics of included studies .................................................................. 106

VII

List of Tables

Table 1: Assessment of methodological quality of included studies ....................................... 36

Table 2: Curcuminoids vs Placebo-controlled studies............................................................. 39

Table 3: Curcumin Vs Active control studies ........................................................................... 44

Table 4 Curcuminoid/complex mixture vs placebo or active control........................................ 50

List of Figures

Figure 1: Prisma Flow Diagram .............................................................................................. 35

VIII

Abstract

Musculoskeletal pain creates a serious burden on quality of life across the globe. Its

management represents a significant economic cost and monopolizes the time and attention

of practitioners involved in medicine and complementary health. Substantial numbers of

people use nutraceuticals and traditional remedies to assist in musculoskeletal pain

management and improvement of function. Curcuminoids are one group of nutraceuticals

which are gaining in popularity and being used for treating musculoskeletal pain.

Curcuminoids are extracted from turmeric, which itself is a traditional botanical remedy. The

aim of this thesis was to assess the effects of the use of curcuminoids on musculoskeletal

pain through a systematic review of the available evidence.

A database search was conducted for studies that assessed the effects of use of

curcuminoids by themselves or in combination with other materials on musculoskeletal pain of

clinical or experimental origin. It included CINAHL, Embase Cochrane Central, Pubmed,

Scopus, Psychinfo and Clinicaltrials.gov. Alternate, traditional medicine and complementary

medicine databases including NCCAM and NICM were searched for additional studies.

Locations for the search for unpublished studies included: Mednar, Proquest theses and

dissertations, Grey Source, Index to Theses, and Trove (Theses).

The reference lists of all identified reports and articles were searched for additional studies.

Studies in English language with human subjects using any form of control including placebo,

treatment as usual and before and after measurements were considered for inclusion in the

review.

No time limit was imposed on studies for inclusion in the systematic review.

IX

Methodological quality of included studies was assessed using the Joanna Briggs Institute

(JBI) critical appraisal checklist, and research data was extracted using the JBI Meta-Analysis

of Statistics Assessment and Review Instrument (MAStARI) data extraction instruments.

Thirteen randomized controlled trials including 1101 participants were included in this review.

The overall quality of included studies was variable. Treatment duration ranged from 10 days

to 32 weeks in the studies and included different dosages and presentations of curcuminoids

and differing comparators. A high level of heterogeneity between studies and characteristics

precluded meta-analysis of findings; therefore, a narrative analysis was presented.

The major finding from the review was that there is currently insufficient evidence to support

the effectiveness of the use of curcuminoids in musculoskeletal pain states. Interpretation of

this finding needs to be considered in the context of significant limitations imposed by the

variable quality of relevant studies, small sample sizes and the small number of relevant

studies available for examination. The systematic review found that in the studies examined,

the frequency or severity of adverse events relating to the use of curcuminoids was not

significantly different from placebo or other study comparators. The findings from the

systematic review support the claims of safety in the literature. The absence of long-term

follow-up across all studies means that comment on the long-term effect of and safety of the

use of curcuminoids in musculoskeletal pain requires further clarifying research.

X

Declaration

I, Andrew Gaffey, certify that this work contains no material that has been accepted for the

award of any other tertiary institution, and, to the best of my knowledge and belief, contains no

material previously published or written by any other person, except where due reference has

been made in the text. In addition, I certify that no part of this work will, in the future, be used

in a submission for any other degree or diploma in any university or other tertiary institution

without the prior approval of the University of Adelaide and where applicable, any partner

institution responsible for the joint award of this degree.

I give consent to this copy of my thesis, when deposited in the university library, being made

available for loan and photocopying, subject to the provisions of the Copyright Act 1968. I also

give permission for the digital version of my thesis to be made available on the web, via the

university’s digital research repository, the library catalogue and also through web search

engines, unless permission has been granted by the university to restrict assess for a period

of time.

Andrew Benedict Gaffey

8th August 2016

XI

Acknowledgements

It is with gratitude I acknowledge my supervisors, Dr Jared Campbell, Dr Kylie Porritt and

Associate Professor Helen Slater for their comprehensive advice and support. They have

been constant in their wisdom, patience and humour in guiding me through this thesis.

I wish to acknowledge the valuable assistance given to me by my co-reviewer, Kishani

Townshend in reviewing the retrieved studies.

I would like to extend my thanks to my family for their enthusiasm and sustained energy over

the duration of my candidature.

1

Chapter 1: Introduction

1.1 Overview

Musculoskeletal pain creates a serious burden and impediment to the enjoyment of life across

the globe. The one-year prevalence of experiencing some form of musculoskeletal pain in the

previous week appears to range between about 14% and 47% of the general population,1 with

most people experiencing musculoskeletal pain reporting pain from a number of sites.2, 3 Low

back pain and neck pain together, with the category of ‘other musculoskeletal disorders’,

constituted three of the top ten leading causes of global years lived with disability (YLD) in

2013.4 The category of osteoarthritis (OA), which is itself associated with varying levels of

musculoskeletal pain, climbed three places from 16th to 13th as a leading cause of global YLD

from 1990 to 2013.5

The management and reduction of musculoskeletal pain represents a significant economic

burden and monopolises the time and attention of practitioners involved in medicine and

complementary health management. Practitioners face decisions every day concerning which

measures at their disposal would be most effective for pain management while at the same

time endeavouring to achieve the best health outcomes for their clients. Movement-based

treatment approaches such as physiotherapy in the form of joint mobilising, muscle stretching

and exercise therapy are successfully used to treat and rehabilitate painful musculoskeletal

conditions. These movement-based approaches are often combined with pharmaceutical pain

control; however, the most effective pharmaceutical pain control does not necessarily result in

the best long-term health outcomes.

At present, paracetamol (acetaminophen)6 and non-steroidal anti-inflammatory drugs

(NSAIDS) are frequently recommended as first-line analgesic treatments for osteoarthritis and

2

other musculoskeletal pain states.7 However, there is uncertainty over the safety and/or

efficacy of paracetamol8 and NSAIDS9 in treating conditions such as osteoarthritis and low

back pain. Long term paracetamol use has been associated with abnormal results on liver-

function tests8 and regular/any use of both paracetamol and NSAIDS is associated with an

increased risk of kidney cancer.10 NSAIDS are among the medicines most frequently

associated with increased cardiovascular events and hypersensitivity reactions11 and have

been found to increase the risks of upper gastrointestinal bleeding with use.12-15 Non-selective

NSAIDS intake is associated with increases in the risk of post-operative bleeding compared

with placebo.16

Substantial numbers of people with musculoskeletal pain use other potential sources of pain

relief including complementary and alternate medicine (CAM) and traditional remedies.17, 18

The US National Centre for Complementary Medicine and Alternative Medicine (NCCAM)

defines CAM as “the use of products or practices in medical practice that are not considered

mainstream”.19 The percentage of the adult population in western countries using

nutraceuticals, CAM or alternative dietary supplements has been variously quoted as close to

40%20 and as much as 47%.21 Those numbers appear to be growing. Chronic

musculoskeletal pain is the single-most quoted reason (in the UK) for patients to use

complementary and alternate medicine.22

Curcuminoids are one group of nutraceuticals gaining in popularity and being used as an

adjunct to, but also as an alternative, to conventional treatments for musculoskeletal pain.

Curcuminoids are extracted from turmeric, which itself is a traditional botanical remedy.23

Turmeric has a number of traditional uses including pain relief as well as for anti-inflammatory

effects.24 Curcuminoids are considered to constitute the majority of the bioactive fractions of

turmeric25 and to have anti-inflammatory effects.26, 27

3

The focus of this thesis is to assess the effects of the use of curcuminoids on musculoskeletal

pain through a systematic review of the available evidence. The aim of the thesis is to advise

and inform clinical practice on, and to identify areas of future research in the field of

curcuminoid use in musculoskeletal pain states.

1.2 Structure of the thesis

The thesis is structured in four chapters:

The first chapter (introduction) is aimed to introduce the topic by firstly giving an historical

context to the use of curcuminoids and their parent plant turmeric, then outlining the

curcuminoid fractions of turmeric, their potential bioactive effects and possible mechanism of

action through pain modulation. To do this, an understanding of pain mechanisms and

musculoskeletal pain is elaborated and given context. The introduction then continues with an

explanation of common standardised measurement tools used for pain and function. Pain and

function were the primary outcome measures of the systematic review on which the thesis

rests.

The introduction concludes with a structured discussion on evidence-based medicine and the

place of primary and secondary research. This part holds an explanation of the power and

worth of systematic reviews and their methods. It serves to justify the construction of the

systematic review, and points to the gap in literature which is filled by the review.

The second and third chapters constitute the methodology and results of the systematic

review on the effects of curcuminoids on musculoskeletal pain. This section includes the

PRISMA flow diagram, tables elaborating the assessment of methodological quality of the

included studies and study characteristics of all included studies, and a narrative summary of

the results of the individual studies.

4

The fourth chapter of the thesis constitutes the discussion of the thesis topic commencing on

the broad fronts of musculoskeletal pain control, curcuminoid use and bioavailability, then

narrowing to study heterogeneity and sources of bias and pain measurement. The thesis

discussion then covers limitations of the systematic review, suggested areas of future

research, (both primary and secondary), recommendations for practice and a final conclusion.

Referencing and appendices follow the conclusion of the thesis.

1.3 Historical context- Curcuminoids and Turmeric

Curcuminoids were isolated and the chemical structures identified by Polish chemists

Milobedska and Lampe in 1910.23, 28 Curcuminoids are polyphenols which come from the

turmeric root. Curcuma longa (turmeric) from the Ginger family (Zingiberacea) is a plant native

to Southeast India which has been used for centuries in cooking and in medicine.28-31 In

cooking, turmeric’s common use is as a spice for flavouring and colouring of foods. The root

is the portion of the turmeric plant which is most commonly used. It is grated fresh or dried

then grated to form a yellow-orange powder. The leaf is used to wrap foods in the cooking

process and also to protect foods in transport.32

Freshly grated turmeric root has a characteristic bright yellow-orange colour while the colour

of the dried grated root is a duller orange. The majority of the colour of the grated root comes

from one of the three bioactive polyphenol curcuminoids of turmeric called curcumin.33

Turmeric is coded in the International Numbering System for Food Additives (INS) as E100(ii).

Curcumin is coded as E100(i).34

It is generally accepted that turmeric intake in South-East Asian and Middle-Eastern countries

is higher than in western countries.35, 36 It is usually consumed in curries and dhals with

average daily intakes per person in regions in India being variously quoted as 0.6g37 and

5

0.9g35 to 2-2.5g.36 Korean daily intake of turmeric per person in the period 2008-2012 was

estimated as 0.47g.38

Historically, turmeric has been used medicinally to assist in the control of inflammation,39 and

pain.40, 41 The methods of delivery of the bioactive substances for medicinal use include being

eaten, or being applied to the skin, gums42 or wounds43 as a paste,44, 45 poultice, or gel.46

Anecdotally, inhalation of burning turmeric smoke has been recorded as a folk-remedy for

respiratory illnesses in humans, and recent studies have examined the effectiveness of

curcumin inhalation for airway inflammation in horses47 and inhalation for potential Alzheimer’s

treatment in mice.48

1.4 Polyphenols

To understand curcuminoids and their effects, it is useful to appreciate that curcuminoids,

isolated from turmeric, belong to a larger group of substances with studied bioactive effects

called polyphenols. Polyphenols are naturally occurring compounds found in fruits, vegetables

and grains.49, 50 There is evidence to suggest that polyphenols are produced by plants for

protection from damage by ultraviolet radiation and to deter predators.51, 52 As such,

polyphenols as a group are seen to possess antioxidant and anti-inflammatory properties

dependent upon their individual chemistry.53 Foods regularly consumed by humans which

have been shown to be high in polyphenols include red wine, green and black tea,49 cocoa,50

fruits (such as grapes, cherries and apples52), some spices52 and grains. There are four

groups of polyphenols which include flavonoids such as quercetin; phenolic acids; stilbenes,

such as resveratrol found in grapes, and lastly; lignans, several of which are phytoestrogens.49

6

1.4.1 Polyphenols and inflammation

The intake of polyphenols has been shown to have various effects in tissues including

antioxidant and anti-inflammatory effects. Antioxidants in general work to remove free radical

intermediates, and inhibit other oxidation reactions by being oxidized themselves.51

Polyphenols from turmeric have been shown in vitro to exert free-radical scavenging activity.54

A bovine study showed curcumin to have antioxidant activity similar to Vitamin C, and

considerably higher antioxidant activity than Vitamin E.55, 56 Many studies have investigated

the potential effects of polyphenols on the inflammatory relationship with increased polyphenol

dietary intake associated with decreases in markers of low-grade inflammation.57

There appears to be methodologically sound evidence from large studies demonstrating the

relationship between the consumption of a polyphenol-rich diet and the reduction of the risk of

chronic conditions such as obesity and cardiovascular disease in humans. 58-60 Such chronic

diseases have a common link of showing elevated inflammatory markers.61-63 Polyphenols

have well-documented effects on down-regulating inflammatory pathways as discussed

above64, 65 and it is plausible to consider the disease-risk reduction seen with the consumption

of polyphenol-rich diets is linked to this reduction of low-grade inflammation.66 Results from

the PREDIMED study showed that specific categories of polyphenols have differing degrees

of action in reducing cardiovascular risk,67, 68 with the intake of nuts,69-74 olive oil69, 72, 75 and

red wine76, 77 featuring as significant contributors to the benefits of the Mediterranean diet.

McKeown et al.50 determined that polyphenol-rich foods can effect a significant improvement

in endothelium-dependent vasodilation following an 8-week intervention in hypertensive

participants. This indicates that a simple change to diet (increasing the intake of polyphenol-

rich foods) can have a significant positive effect on markers of cardiovascular risk.

7

1.4.2 Polyphenols, inflammation and pain

The link between pain and inflammation varies, as pain is not influenced by tissue factors

alone. Inflammation and the associated inflammatory process is mediated by a number of key

chemicals in the body, some of which can sensitise or excite specialised nerve endings called

‘nociceptors’ on A delta and C sensory nerve fibres.78-80 These are nerve fibres that transmit

information to higher centres, which in turn, may be interpreted by the brain as pain. Kidd and

Urban81 relate the experience of pain to activity in the nociceptive system, with this activity

resulting from endogenous (within the body) and exogenous (external to body) sources. They

include inflammation as an endogenous stressor which occurs in response to tissue damage

and typically this is associated with pain.

There are various studies utilising rat models that investigate the effects on the ingestion of

polyphenols as a group on certain types of pain. Yin et al82 found that the polyphenol

resveratrol appeared to facilitate pain attenuation behaviours in a rat model of neuropathic

pain, and in an unrelated study, resveratrol was able to reduce levels of pro-inflammatory

cytokines in vitro and showed pain-reduction potential in a rat model of radiculopathy.83

There is little discussion in the literature directly investigating the effect of polyphenols as a

group in modulating pain in humans. A small study (utilising14 subjects with limited range of

motion (ROM); most with OA) investigated the effect of a polyphenol-rich blend of fruit juices

and pulp on pain and range of motion.84 It was found that in people with limited range of

motion improvements in serum antioxidant status correlated with improvements in pain and

ROM.84 The authors concluded that the reduction of pain in vivo may have been due to

resveratrol reducing pro-inflammatory cytokines.83

8

1.5 Curcuminoids- the Polyphenols in Turmeric

Turmeric contains at least three naturally-occurring polyphenols termed curcuminoids;

curcumin, demethoxycurcumin and bisdemethoxycurcumin.28 Various studies describe the

total curcuminoids by percentage in the turmeric root as falling between 3% and 6% of dry

weight. 85, 86 Curcumin is by far the most prevalent curcuminoid found in turmeric,39 making up

around 77% of the total curcuminoids in the plant. Demethoxycurcumin makes up about 17%

of the total curcuminoids and bisdemethoxycurcumin about 5% of the total curcuminoids.

Curcuminoids are ascribed antioxidant properties87 and anti-inflammatory properties.26, 56

Ahmed and Gilani88 acknowledge that scientists in some studies use the name of curcumin

and curcuminoid mixture (also known as commercial curcumin) interchangeably. They go on

to examine in their Alzheimer’s Disease review the pharmacodynamic properties of curcumin

and curcuminoid mixtures used in various studies and include comment on the respective

purities of the compounds. Note that curcuminoids can be isolated from ground turmeric

powder in various ways. A common method is an industrial process of steam separation

and/or distillation using isopropyl alcohol.89, 90 This processing serves to concentrate the

curcuminoids into a crystalline form. This is not a simple process, and the purity of compounds

used in studies with respect to particular amounts of the three fractions of curcuminoids

finding their way into the mixture is often not stated.88 For this thesis, a decision has been

made respecting the variability of descriptors used in literature. The decision is that unless the

study refers specifically to curcumin or another curcuminoid by name as being the only

curcuminoid present in the sample used in the study, the term ‘curcuminoids’ will be used

when commenting on that study. In studies where the authors have made it clear that a

specific curcuminoid has been used, then the specific descriptor of that particular curcuminoid

will be used in the thesis. Conversely, in studies where the authors have used the descriptor

9

“curcumin” but have clearly stated that a mixture of curcuminoids was used, then references in

this thesis to that study’s active treatment material will be ‘curcuminoids”.

1.6 Postulated Bioactive effects of Curcuminoids

Curcuminoids are postulated to have various bioactive effects, with various animal studies

showing effectiveness in the treatment of joint inflammation,91, 92 experimentally-induced

rheumatoid arthritis,93 depression,94 burn pain,95 the reduction of serum triglycerides,96

peripheral neuropathy97, diabetic neuropathic pain98-100, sciatic nerve chronic constrictive

injury resulting in neuropathic pain101, experimental acute pancreatitis102-104 and enhancing

wound-healing.95, 105

The effects of curcuminoids have also been assessed in insect studies. Fruit-flies (Drosophila)

fed curcumin-supplemented diets showed increased mean life-span compared with Drosophila

fed curcumin-free diets.106, 107In an interesting vector-control study, curcuminoids showed

significant larvacidal activity against the mosquito.108In a study assessing termite control, non-

curcuminoid fractions of turmeric were found to have termicidal properties.109

Other than musculoskeletal pain, human studies investigating the effects of curcuminoid

polyphenols identify significant bioactive effects of curcuminoids on inflammation by reducing

mastitis,110 spermatic cord inflammation,111 dermatitis due to radiation exposure112 and large

bowel inflammation.113

Active metabolites of curcuminoids are produced after oral doses of curcuminoids have been

ingested.114, 115 These include tetrahydracurcumin and hexahydrocurcumin. There is some

debate in the literature concerning whether one or all of the curcuminoids, or a specific

10

metabolite of one or all of them, may be responsible for the bioactive effects seen with the use

of turmeric and curcuminoids.114

1.7 Bioavailability of Curcuminoids

For curcuminoids to have an effect in the body they need to be absorbed. Curcuminoids are

relatively hydrophobic and poorly absorbed.86, 115, 116 Compounding these difficulties is the fact

that curcuminoids are swiftly eliminated from the body.117, 118 The resultant effect is that

curcuminoids have a low bioavailability in the body after ingesting or exposure by other

means.

However, bioavailability of curcuminoids can be enhanced in various ways. One method is to

reduce their hydrophobic nature and enhance their solubility in water. A 12-fold increase in

solubility was claimed after heating a curcumin solution in water to boiling for 10 minutes.119,

120 Another method to increase bio-availability is by combining the curcuminoids with or co-

administering them with adjuvants.121, 122 Curcuminoids can be rendered into nano-particles,

bio-optimised by complexation, or used as liposomal curcumin.

1.7.1 Adjuvants

An adjuvant is a substance that augments the action of a medication or other agent.123

Adjuvants are sometimes termed bio-enhancers.124 In the case of curcuminoids, adjuvants are

believed to be important as they can interfere with the enzymes that catalyse the metabolising

of curcuminoids, thereby increasing bioavailability.125-127

Piperine (l-piperoylpiperidine) is an adjuvant commonly used with curcuminoids. Piperine is

itself a plant extract from Black Pepper (Piper Nigrum Linn.) or Long Pepper (Piper Longum

Linn.). 125, 127 Piperine preparations inhibit glucuronidation,86 and have been shown to increase

bioavailability of curcumin by up to 20-fold.86

11

1.7.2 Nanoparticle preparations

Nanoparticle preparations of curcumin (where the particle size has been maintained below

100nm and held in a suspension or gel)116 have been found to increase bioavailability 9-fold

compared with curcumin-piperine combinations121. They appear to do this by providing more

penetration to membrane barriers due to their reduced size.25 A way of producing nanoparticle

preparations is by dissolving curcumin and polymer in ethyl acetate and stirring, adding the

mixture to an aqueous solution containing a stabiliser to form an emulsion, and then

homogenising the emulsion followed by further dilution with the final result of nano-

precipitation.128

1.7.3 Complexation

Complexation is the combination of individual atom, ion or molecule groups to form one big

molecule. Phytosomes are the combination of a natural active ingredient (for example,

curcumin or other curcuminoids) with a phospholipid.123 The complexation of curcuminoids

into phytosomes has been shown to improve bioavailability of curcuminoids by increasing their

absorption.129, 130 As a result, commercial preparations of curcuminoids are often combined

with a surfactant such as polysorbate and then termed “bio-optimised”.131, 132

Another material apart from polysorbate used to produce a phytosome with curcumin is

phosphatidylcholine. Rat studies show that curcumin formulated with phosphatidylcholine

furnishes higher systemic levels of curcumin than unformulated curcumin.133 Uncontrolled

human studies claim that such phytosomes are safe to use and increase the absorption of

curcumin.134

1.7.4 Non-Curcuminoid portion of turmeric extract

There is evidence that suggests that the non-curcuminoid portion of turmeric increases or

potentiates the effects of curcumin.121, 135, 136 Some emerging evidence suggests that the non-

12

curcuminoid portion of turmeric extract can deliver an anti-inflammatory effect of its own;

distinct from the effect noted from curcuminoids.137-139

1.8 Pain and Definitions

Pain is defined as an unpleasant sensory and emotional experience associated with actual or

potential tissue damage, or described in terms of such damage by the International

Association for the Study of Pain (IASP) Task Force on Taxonomy 1994.140, 141 The human

experience of pain is multidimensional and comprises sensory, affective, and cognitive

dimensions.142 Acute pain is pain which is recent in onset, typically but not always,

proportional to cause143 and disappears with the resolution of the pathological process.144

Chronic pain is defined as pain that has lasted longer than 3 months or beyond the expected

time for tissue healing.145 Pain can be experienced in the absence of tissue damage.146 Pain

is always subjective and as such is difficult to quantify.146

Tissue damage results in a myriad of physical and chemical effects in the body. Amongst

these effects, if tissue injury is sufficient in magnitude and duration nerve terminals called

nociceptors depolarize. At the site of tissue injury various neuropeptides are released which

can sensitize/excite nociceptors and increase the rate of neuronal firing.80 Inflammatory

mediators such as bradykinin, prostaglandins and pro-inflammatory cytokines released in the

area, augment the transmission of nociceptive impulses along sensory afferent fibers147 to the

spinal cord (second order neurones) and up to higher brain centres. Whether the sensory

impulses are registered by the brain as pain depends on many factors, as nociception and

pain are not synonymous: pain can exist with or without nociceptive input and nociception can

exist without pain.80, 146

13

Pain associated with tissue damage and inflammation is frequently termed nociceptive

inflammatory pain. It is caused by activation of the immune system148 and characterised by the

presence of various chemicals including inflammatory cytokines.149 Resveratrol,49 and

mangiferin150 have been shown to modulate the production of inflammatory cytokines.

Evidence in tumour studies demonstrates that the anti-inflammatory effect of curcuminoids is

likely to occur through markedly inhibiting the mRNA and protein expression of

cyclooxygenase-2 (COX-2)151, and by inhibiting lipogenase (LOX) and inducible nitric oxide

synthase (iNOS).56, 152 Additionally, murine studies have demonstrated a reduction of

inflammatory cytokine expression in adipose tissue with the administration of nutritional doses

of curcumin and piperine.127

In summary, various studies show curcuminoids can have an anti-inflammatory effect and

therefore the potential exists to ameliorate pain which arises from inflammation. No studies

were found which hypothesized on any potential mechanism by which curcuminoids could

ameliorate chronic pain occurring in the absence of tissue inflammation.

Musculoskeletal pain is the clinical description of non-cancer pain associated with bone, joint

and muscular tissues123 including joint sprains and soft tissue strains, pain associated with

joint degeneration and osteoarthritic conditions, as well as pain associated with inflammatory

conditions such as rheumatoid arthritis (RA). Neuropathic pain (defined as pain caused by a

lesion or disease of the somatosensory system153) has clinical examples that in the strictest

sense can fit the definition of musculoskeletal pain. However, as it is considered a “stand-

alone” type of pain condition, for this study it has been excluded from consideration.

14

1.9 The Effects of Curcuminoids on Inflammation

The effects of curcuminoids on inflammation have been well investigated in animal studies.

Rat studies show curcumin has an anti-inflammatory effect on sciatic-nerve constrictive

injuries,101 has anti-nociceptive effects by probable inhibitory effects on c-Jun N-terminal

kinase (JNK) and extracellular signal-regulated kinase (ERK),154 as well as decreasing neuro-

inflammation in diabetic neuropathy.155 Murine studies show reduction of neuro-inflammation

due to intervertebral disc herniation with the administration of elastin-like polypeptide-curcumin

conjugates delivered into the perineural space.156 A hamster study showed curcuma oil

attenuates arterial injury-induced accelerated atherosclerosis, inflammation and macrophage

foam-cell formation.157

Human in-vitro studies show curcuminoids can reduce inflammation in human intervertebral

disc cells.158 A recent review by Shezhad, Rehman and Lee40 discussed the use of curcumin

in inflammatory diseases, and acknowledged its effects while citing numerous studies.

1.10 Outcome measures relevant to musculoskeletal pain

The systematic review protocol stipulated that the systematic review would consider studies

which assessed the effects of curcuminoids on musculoskeletal pain. The protocol stated the

primary outcome measures of visual analogue scales (VASs) and/or questionnaires would be

considered. The protocol was constructed thus for two reasons. Firstly, studies of effect of a

treatment on musculoskeletal pain require reliable, valid tools for standardising measurement

of pain to produce data, and secondly, VAS, numerical rating scales (NRS) and

questionnaires are the tools commonly used clinically and are the tools commonly represented

in studies dealing with musculoskeletal pain.159

15

The experience of pain, (as discussed in Chapter 1.8) is subjective and complex160 and not

easy to quantify. VAS and NRS have been developed to allow measurement of subjective

conditions such as the experience of pain and therefore allow comparisons to be made

between discrete time frames and differing treatments.161 VAS are considered valid and

reliable in the measurement of parameters of such diverse conditions as chronic162 and acute

pain,163, 164 mountain sickness165, cervical radiculopathy166, Botulinum A toxicity in the

treatment of cerebral palsy,167 nasal obstruction,168, 169 anxiety170 and acute abdominal pain.164

Visual analogue scales are typically, horizontal or vertical lines 10cm (100mm) long with

identified start and finish anchors.171 Standard descriptors of the anchors are used to guide

the user. These descriptors are typically “no pain at all” and “pain as worse as it could be” on

the left and right line extremes respectively.172 NRS have also been validated for

measurement of pain in a variety of circumstances and conditions similar to VAS. NRS are

usually scales of numbers ranging from 0-10 with a descriptor at either end similar to

descriptors used in VAS. One study included in the systematic review used a 12-point

numerical scale 1-12.173 Studies comparing accuracy and interchangeability of VAS and NRS

are not consistent in their recommendations for use for one in preference to another in all

cases. Both seem reasonably valid and useful for pain assessment, with a recent review by

Hjermstad et al.161 stating that NRS is applicable for the unidimensional assessment of pain

intensity in most settings.

Various questionnaires are used in the musculoskeletal setting, with those most frequently

encountered being involved with the assessment of disability as opposed to the assessment of

the pain experience or levels of pain. Many are validated and considered reliable; focussing

on a range of applications including low back disability; such as the Owestry Disability Index

(ODI), and the Roland-Morris Disability Questionnaire (RDQ).174

16

In summary, the quantifying of musculoskeletal pain states is complex and difficult. Various

assessment tools are in common use, with VAS and NRS not only the most common, but

considered the one of the most reliable for the assessment of pain intensity or severity in

numerous different settings and conditions.

1.11 Validated measures of function

Numerous different evaluation systems exist to assess function. Some are specific to certain

disabilities, others to upper or lower limb function or to age groups. The Western Ontario and

McMaster Universities Arthritis Index (WOMAC) was developed at the Western Ontario and

McMaster Universities as a standardised and functional assessment questionnaire tool for use

in primarily in hip and knee OA trials.175, 176 This tool is used to assess function on four arms

and has been seen to be repeatable and accurate across populations and age groups.177 It is

simple and quick to administer, and using individual scores for each subscale rather than an

aggregate score enhances interpretation.178 The WOMAC is a commonly-used assessment

tool178 and four of the studies173, 179-181 included in the systematic review used WOMAC to

assess function.

The Japanese Knee Osteoarthritis Measure (JKOM) is an evaluation score for OA that is

patient-based with four subcategories: pain and stiffness (JKOM-pain; total of eight questions,

0-32 points), activities of daily living (ADL) score (total of 10 questions, 0-40 points),

participation in social activities score (total of five questions, 0-20 points), and general health

conditions (total of two questions, 0-8 points) with 100 points as the maximum score. The

higher the JKOM score; the more pain and physical disability is experienced by the patient.182

This evaluation modality has been shown to have reliability and validity through statistical

evaluations and comparison with the Western Ontario and McMaster Universities Arthritis

17

Index (WOMAC) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-

36).182, 183 JKOM was used to measure function in one study184 included in the systematic

review.

Lequesne’s pain functional index (LPFI) is a validated ten-question survey scored on a 0-24

scale, used to assess function in OA of the knee.185, 186 It was used in one study included in

the systematic review as an outcome measure for the assessment of function.180 The LPFI

has been rated against the WOMAC and VAS for sensitivity to change187 and also shown to

have convergent validity against the Thai-modified WOMAC index.188

The KOOS (Knee injury and Osteoarthritis Outcome Score) is a score obtained from a

questionnaire that was developed in Swedish and English to be used for short- and long-term

follow-up of knee OA and knee injury.189 The KOOS is made up of five separately scored

subdomains, based on 42 individual items. The subdomains are symptoms (seven items),

pain (nine items), activities of daily living (ADL) (17 items), function in sport and recreation

(five items) and knee-related quality-of-life (QoL) (four items). Each item is scored from 0

(least severe) to 4 (most severe).178, 189, 190 The KOOS has been validated against the

WOMAC in total knee replacement189 and as an instrument to measure the clinical outcome

after the treatment of a focal, symptomatic cartilage defect in the knee.191 It has been

validated as an instrument to measure clinical outcome after arthroscopy of the knee.192, 193

Translations have been validated for use in knee injury and osteoarthritis for speakers of many

languages including Polish,194 Singaporean English and Chinese,195 Swedish,192 Greek196 and

Spanish193. The KOOS was used in one study included in the systematic review as an

outcome measure for the assessment of function.197

18

The DAS28 is an index used to assess RA that combines information from swollen joints,

tender joints, acute phase response and general health.198 It is one of the most commonly

used composite scores in clinical practice.199 It can be used to assess changes in a patient’s

condition compared with a baseline. Higher scores indicate higher disease activity.200 The

DAS28 index was developed from the DAS and has been validated201 but at least one study

expresses caution as to its reliability.202 The DAS28 was used in one study203 in the

systematic review as an outcome measure to assist in assessing changes in function.

The HAQ (Health Assessment Questionnaire) is a functional measure designed to help

assess RA in both clinical and research circumstances.204 It is a questionnaire first developed

at Stanford University in 1978 by James Fries and colleagues with the initial paper published

in 1980.205 The HAQ is available in over 60 languages and is typically used in two formats.206

The full version of the HAQ collects data over 5 generic patient-centered health dimensions.207

These dimensions include functional disability, pain and discomfort, adverse effects of

treatment, costs and premature death.206, 208, 209 The short (2 page version) HAQ is most

commonly used and includes the HAQ Disability Index, the HAQ pain scale (VAS), and the

VAS global health scale.206 The short version HAQ has been validated and culturally adapted

for use in many languages apart from English,209 including Bengali,210 Thai208 and Chinese.211

The HAQ Disability Index was used by one study203 included in the systematic review as an

outcome measure to assist in assessing changes in function.

In summary, there are numerous validated scales used to assess function in literature. The six

outcome measures of function used in the studies included in the systematic review are

discussed above. They all have been validated and are considered to have reliability and

repeatability.

19

1.12 Evidence-based medicine and systematic reviews

Medical and allied health practice is guided by consideration of evidence to support or

disprove a particular management or treatment method. Evidence-based medicine is defined

as the explicit, conscientious and judicious attempt to find the best possible available research

evidence to assist the health professionals to make the best decision for their individual

clients.212 Such evidence is accumulated from research studies designed to test hypotheses of

treatment; examine result data before and after treatment, or studies aimed to gather

observations of relevant treatment methods and cases.

Previously, the collection of evidence for the support or clarification of a particular treatment or

procedure was an ad-hoc process. Individuals would gather studies from publications and

journals available to them at the time and collate information from those studies based on their

own specific needs and biases. This information would be allied to knowledge based on

experience and anecdote, as well as received wisdom from tradition and folklore. Decisions to

favour a particular treatment or procedure as such were not necessarily reliable or consistent

and fraught with the potential for numerous forms of bias.213

More recently, secondary research in the form of reviews of literature have added to the body

of evidence. Reviews of literature endeavour to collate in one publication narrative, summaries

of studies relevant to one area of investigation. They have assisted decision-making by

clinicians through the localisation and synthesis of information and results data. These reviews

do not involve a systematic search of the literature and can often include an element of

selection bias.214

Systematic reviews take secondary research one step further. The method of what now

constitutes a systematic review (see below in 1.12.1 The Principles of the Systematic Review)

20

was formally advocated by the Cochrane collaboration after the establishment of the

Cochrane Centre in Oxford in October 1992.215 This centre continues to carry out systematic

reviews to the present day which are published in the Cochrane Library. In addition to

Cochrane there are organisations that contribute to the development of systematic review

methodology, the Joanna Briggs Institute (JBI) being one of them. The JBI, is a not-for-profit

research and development organisation within the Faculty of Health Sciences at the University

of Adelaide and has been active in the field of global translation of research evidence into

practice since 1996 and publishing systematic review reports in various formats since 1998.216

JBI works closely with Cochrane and the Campbell collaboration and utilises similar

methodology in systematic reviews. JBI systematic reviews are commonly published in the JBI

database of systematic reviews and implementation reports.216 The systematic review

discussed in this thesis utilised the recommended methodology of JBI for reviews of

effectiveness.(see Principles below 1.12.1)

1.12.1 The Principles of systematic review

Aromataris and Pearson217 remind the scientific community that a systematic review will

influence health care decisions and as such should be conducted with the same rigor

expected of all research. These researchers outline the generally-accepted defining features

of the systematic review.

The defining features of the systematic review are:

A clearly articulated question or objective

Inclusion/exclusion criteria stipulated a priori in the systematic review protocol

A comprehensive pre-planned search

21

Appraisal method of the quality of included studies

Analysis of data

Presentation and synthesis of findings

Transparent reporting.217

A clearly articulated question or objective assists researchers in conducting a review but also

assists readers to decide whether to read the review. The question puts the review in motion

and helps the databases in the task of indexing the review.218

Specified, predetermined inclusion/exclusion criteria remove one potential source of reviewer

bias and the predetermination improves transparency of the review.218 The reviewer uses

predetermined inclusion and exclusion criteria to sort the studies.216 The JBI systematic review

guidelines; similar to the Cochrane, require this predetermination and extend it to the data

extraction method.219, 220 Publication of this predetermined systematic review protocol is now

common practice and the protocol for the systematic review on which this thesis was based

was published accordingly in the JBI database of systematic reviews and Implementation

reports.221 The process of publishing the protocol assists in alerting the scientific world of a

forthcoming systematic review on a specific question and avoiding duplication.222 Prospero is

an international registry developed in 2013 to record prospective systematic reviews in Health

and social care, welfare, public health, education, crime, justice, and international

development, where there is a health related outcome.223 Publication of the systematic review

protocol in a registry such as Prospero allows a clear comparison of the predetermined

protocol with the completed review; reducing the opportunity of reporting bias in the completed

systematic review.223

22

In a systematic review, the search terms are predetermined and are systematically applied

across all included databases to identify all relevant studies to the pre-established question.

Strong efforts should also be made to identify any relevant unpublished studies which will

assist in minimising the potential for publication bias in the review.224 Carrying out a

comprehensive database search reduces the potential for assessor bias to influence the

selection of studies as all studies which meet the predetermined criteria should be identified

and selected. This approach allows the search to be repeated and tested.222

Critical appraisal of the selected studies allows sorting and grading of the studies for

inclusion.224, 225 The use of the same critical appraisal checklist or tool across the studies

reduces the potential for reviewer bias and assists the systematic review to present a

transparent and repeatable method.214, 226 The Cochrane tool has become the standard

approach to assess risk of bias in randomized clinical trials but is frequently implemented in a

non-recommended way.227 Any assessment tool or checklist used in a systematic review

needs to be implemented in a consistent and transparent fashion.227, 228

Analysis of data extracted from the included studies follows critical appraisal and sorting of the

studies.213 The extracted data will include details of the participants, interventions,

comparators and outcomes (i.e. the PICO) with the outcomes those predetermined and

published in the protocol.

1.12.2 Systematic Reviews assist in establishing evidence-based medicine guidelines

A major value of systematic reviews is in establishing evidence-based guidelines. Systematic

reviews use a specific predetermined format to conscientiously and judiciously assess the

value of evidence from all the primary studies which have met the stated inclusion criteria.222

Grading the quality of evidence and the strength of recommendations is commonly carried out

23

utilising the GRADE system229 which is seen to provide the highest levels of trustworthy

comment on strength of evidence.226 Evidence-based guidelines are able to include data from

other non-systematic and systematic reviews to assist in forming recommendations, guidance

and conclusions. The construction of evidence-based guidelines is reliant on best-evidence

synthesis using methods which minimise the potential for all forms of bias.216 Systematic

reviews provide the strongest and most-defensible sources of evidence on which to base

these syntheses.

In the case of the use of turmeric and curcuminoids, there is a long historical record of use in

traditional medicine to help achieve various desirable outcomes31, but a lack of high quality

studies and evidence of effectiveness. Studies such as the systematic review under

discussion are aiming to contribute to evidence-based guidelines for the use of turmeric or

curcuminoids in musculoskeletal pain states. At present, there are no evidence-based

guidelines for the use of turmeric or curcuminoids in the clinical management of

musculoskeletal pain states. Many claims of effectiveness are made in the popular media

based on animal studies or human studies with high potential for bias and poor or no controls.

1.13 Gap in the literature

The aim of this study is to address a gap in knowledge of the potential for curcuminoids to

assist in the management of musculoskeletal pain by systematically reviewing all relevant

studies.

A review of the Cochrane Library, JBI Library of Systematic Reviews, CINAHL, and other

relevant databases did not find any past, current or planned systematic reviews on this topic.

24

Related recent non-systematic reviews included Jurenka,39 Shen et al.49 and Gupta et al.230

Recent related systematic reviews by Lakhan et al.231 and Sahebkar and Henrotin.232 included

heterogeneous meta-analyses and had significant differences in focus.

Jurenka reviewed the anti-inflammatory properties of curcumin; acknowledging its potential as

a therapeutic agent for a variety of inflammatory conditions.39 Shen et al. reviewed the effects

of commonly consumed polyphenols on mechanisms of osteoarthritis and identified that the

beneficial effects of curcumin can be achieved through dietary supplementation.49 Gupta et

al.230 reviewed the therapeutic roles of curcumin in specific diseases and conditions through

the examination of clinical trials. Their review commented on a variety of topics which included

arthritis, alcohol intoxication, Alzheimer’s disease, lupus and numerous other conditions but

did not include specific investigation on the role of curcuminoids in treating musculoskeletal

pain. In their review, Gupta et al.230 concluded that curcumin’s effects may be linked to

modulation of numerous signalling molecules considered key to sensitisation processes

associated with pain.230 The systematic review by Lakhan et al.231 examined the effects of

Zingiberaceae (the botanical Ginger family as a whole which includes turmeric) extracts for

pain and concluded they are effective hypoalgesic agents (reduce tissue sensitivity) with a

better safety profile than NSAIDs drugs.231 The Lakhan et al.231 review differed from the

Gaffey et al.221 systematic review upon which this thesis is based as the Gaffey et al.221

systematic review specifically focussed on examining the effects of curcuminoids on

musculoskeletal pain. The Lakhan et al231 reviewers drew the strongest conclusions from a

meta-analysis of the results from eight studies; only one of which assessed the effects of

curcuminoids for pain. Thus, their strongest conclusions had little relationship specifically to

curcuminoids. Additionally, type or category of pain in the Lakhan et al.231 review was not

limited to musculoskeletal pain.

25

Sahebkar and Henrotin232 reviewed the analgesic efficacy and safety of curcuminoids in

clinical practice and carried out a meta-analysis of pain and algofunctional status, using

heterogeneous sources of pain (post-operative, visceral and musculoskeletal), differing

controls (placebo and non-selective NSAIDS: (nsNSAIDS)) and heterogeneous dosages of

curcuminoids and controls. Due to the heterogeneous nature of the controls, pain sources and

dosages of active treatments and controls in the studies examined by Sahebkar and

Henrotin232, their meta-analysis process could have incorporated statistical flaws. This

represents a limitation in their systematic review and questions the results gained from their

meta-analysis.

26

Chapter 2: Systematic Review Methodology

2.1 Review Objective

The objective of this review was to investigate the effect of curcuminoids on human

musculoskeletal pain.

2.2 Criteria for considering studies for this review

This review considered studies that included any humans (children, adults and older people)

experiencing musculoskeletal pain; including experimentally induced pain.

2.2.1 Types of intervention(s)

This review considered studies that evaluated the use of turmeric, turmeric extract or

curcuminoids on subjects experiencing pain of clinical or experimental origin. Where turmeric

or curcuminoids were delivered as one component of a combination of bioactive agents and

not individually controlled for, the studies were included but considered separately.

2.2.2 Types of comparator

This review considered studies with any form of comparator including placebo and active

controls. Studies using before and after measurements and treatment as usual as

comparators were also considered for inclusion in this review.

2.2.3 Types of outcomes

This review considered studies that included the following outcome measures: pain diaries,

visual analogue scales (VASs), or pain questionnaires. Secondary outcome measures of

functionality including activities of daily living and range of motion (ROM) were included. Any

reports or data in selected studies on adverse events were included.

27

2.2.4 Types of studies

A range of experimental study designs including randomized controlled trials, non-randomized

controlled trials, quasi-experimental and before and after studies were eligible for

consideration in this review. Studies published in English were considered without date

restriction.

2.3 Method of the review

This systematic review was carried out in accordance with a published protocol in The JBI

Database of Systematic Reviews and Implementation Reports (registration #1684) and

Prospero Centre for Reviews and Dissemination (reg.#CRD42015019039).221

2.3.1 Search strategy

The search strategy aimed to find both published and unpublished studies. A three-step

search strategy was utilised in this review. Firstly, an initial limited search of MEDLINE and

CINAHL was undertaken followed by analysis of the text words contained in the title and

abstract, and of the index terms used to describe the article. A second search using all

identified keywords and index terms was then undertaken across all included databases. It

searched terms specific and related to Pain, Curcuminoids and their parent turmeric and

Musculoskeletal terms and descriptors.

Using the database “PubMed” as the example, these terms and their relations were expanded

to cover all variations using the data-base specific abbreviations and macros and combined

using Boolean logic terminology (see below) with the resultant located studies being searched

by title and abstract for relevance by the principal reviewer (ABG). This relevance search was

aimed to ensure all studies meeting inclusion criteria proceeded to full-text assessment.

Specifically, due to the large numbers of animal studies published in the field, abstract

28

relevance screening aimed to ensure identification of all human studies in the field potentially

meeting inclusion criteria; excluding animal studies. In addition, the relevance screening of title

and abstract assisted in removing studies which were specific to non-musculoskeletal pain

sources and therefore not meeting inclusion criteria.

PubMed

Pain

("pain"[MeSH Terms] OR "pain"[All Fields]) OR discomfort[All Fields] OR ("nociception"[MeSH

Terms] OR "nociception"[All Fields]) OR ("headache"[MeSH Terms] OR "headache"[All

Fields]) OR (delayed[All Fields] AND ("age of onset"[MeSH Terms] OR ("age"[All Fields] AND

"onset"[All Fields]) OR "age of onset"[All Fields] OR "onset"[All Fields]) AND ("myalgia"[MeSH

Terms] OR "myalgia"[All Fields] OR ("muscle"[All Fields] AND "soreness"[All Fields]) OR

"muscle soreness"[All Fields]))

Turmeric and its active polyphenol curcuminoids

(curcum[All Fields] OR curcuma[All Fields] OR curcumadione[All Fields] OR curcumadionol[All

Fields] OR curcumae[All Fields] OR curcumagalactomannoside[All Fields] OR

curcumagalactomannosides[All Fields] OR curcumal[All Fields] OR curcumalactone[All Fields]

OR curcumalactones[All Fields] OR curcumall[All Fields] OR curcumalonga[All Fields] OR

curcumanggoside[All Fields] OR curcumanoid[All Fields] OR curcumanolide[All Fields] OR

curcumanolides[All Fields] OR curcumara[All Fields] OR curcumas[All Fields] OR

curcumatherapie[All Fields] OR curcumawurzelstock[All Fields] OR curcumazedoaria[All

Fields] OR curcumba[All Fields] OR curcume[All Fields] OR curcumen[All Fields] OR

curcumenal[All Fields] OR curcumene[All Fields] OR curcumenes[All Fields] OR

curcumenoids[All Fields] OR curcumenol[All Fields] OR curcumenolactone[All Fields] OR

curcumenolactones[All Fields] OR curcumenone[All Fields] OR curcumeroid[All Fields] OR

curcumference[All Fields] OR curcumi[All Fields] OR curcumia[All Fields] OR curcumicola[All

Fields] OR curcumimoids[All Fields] OR curcumin[All Fields] OR curcumin'[All Fields] OR

curcumin's[All Fields] OR curcumin1[All Fields] OR curcumina[All Fields] OR curcuminate[All

Fields] OR curcuminato[All Fields] OR curcuminbf2[All Fields] OR curcuminc3complex[All

Fields] OR curcumine[All Fields] OR curcuminiii[All Fields] OR curcuminin[All Fields] OR

29

curcumininduced[All Fields] OR curcumininoids[All Fields] OR curcuminis[All Fields] OR

curcuminkinetic[All Fields] OR curcuminmediated[All Fields] OR curcuminn[All Fields] OR

curcumino[All Fields] OR curcuminoid[All Fields] OR curcuminoides[All Fields] OR

curcuminoidessential[All Fields] OR curcuminoids[All Fields] OR curcuminoids'[All Fields] OR

curcuminoids'components[All Fields] OR curcuminol[All Fields] OR curcuminon[All Fields] OR

curcumins[All Fields] OR curcumintreated[All Fields] OR curcumintreatment[All Fields] OR

curcuminyl[All Fields] OR curcuminylthymidine[All Fields] OR curcuminyluridine[All Fields] OR

curcumisome[All Fields] OR curcumisomes[All Fields] OR curcumnoids[All Fields] OR

curcumoid[All Fields] OR curcumol[All Fields] OR curcumol's[All Fields] OR curcumolhas[All

Fields] OR curcumolide[All Fields] OR curcumone[All Fields] OR curcumonoids[All Fields] OR

curcumorpha[All Fields] OR curcumstances[All Fields] OR curcumurin[All Fields]) OR

("curcuma"[MeSH Terms] OR "curcuma"[All Fields] OR "turmeric"[All Fields])

Musculoskeletal terms and descriptors

("inflammation"[MeSH Terms] OR "inflammation"[All Fields]) OR ("arthritis"[MeSH Terms] OR

"arthritis"[All Fields]) OR ("osteoarthritis"[MeSH Terms] OR "osteoarthritis"[All Fields]) OR

("wounds and injuries"[MeSH Terms] OR ("wounds"[All Fields] AND "injuries"[All Fields]) OR

"wounds and injuries"[All Fields] OR "wound"[All Fields]) OR ("ligaments"[MeSH Terms] OR

"ligaments"[All Fields] OR "ligament"[All Fields]) OR (soft[All Fields] AND ("tissues"[MeSH

Terms] OR "tissues"[All Fields] OR "tissue"[All Fields])) OR ("joints"[MeSH Terms] OR

"joints"[All Fields] OR "joint"[All Fields]) OR ("muscles"[MeSH Terms] OR "muscles"[All Fields]

OR "muscle"[All Fields]) OR ("bone and bones"[MeSH Terms] OR ("bone"[All Fields] AND

"bones"[All Fields]) OR "bone and bones"[All Fields] OR "bone"[All Fields]) OR ("wounds and

injuries"[MeSH Terms] OR ("wounds"[All Fields] AND "injuries"[All Fields]) OR "wounds and

injuries"[All Fields] OR "wound"[All Fields]) OR ("ligaments"[MeSH Terms] OR "ligaments"[All

Fields] OR "ligament"[All Fields]) OR ("tendons"[MeSH Terms] OR "tendons"[All Fields] OR

"tendon"[All Fields]) OR ("fascia"[MeSH Terms] OR "fascia"[All Fields]) OR musculoskeletal[All

Fields] OR DOMS[All Fields] OR (delayed[All Fields] AND ("age of onset"[MeSH Terms] OR

("age"[All Fields] AND "onset"[All Fields]) OR "age of onset"[All Fields] OR "onset"[All Fields])

AND ("myalgia"[MeSH Terms] OR "myalgia"[All Fields] OR ("muscle"[All Fields] AND

"soreness"[All Fields]) OR "muscle soreness"[All Fields]))

30

Other data bases searched as discussed in the systematic review protocol (including CINAHL

and EMBASE) were searched using a similar strategy to that used with PubMed. The CINAHL

search is included as a further example below.

CINAHL

Pain terms

TX pain OR TX discomfort OR TX sciatica OR TX headache OR TX delayed onset muscle

soreness OR SU Pain

Curcuminoid Terms:

TX Curcuminoid OR TX curcuminoids OR TX curcuma longa OR TX turmeric OR SU turmeric

Study references were obtained from combining the above fields using “AND” with a

subsequent hand-search for relevance.

Thirdly, the reference lists of all identified reports and articles were searched for additional

studies not already identified.

Full-text screening was then performed by the principle reviewer (ABG) following the

completion of the three-stage search and relevance search of titles and abstracts. Full-text

screening found any further studies not meeting inclusion criteria and not previously excluded.

As examples, full-text screening facilitated the identification of studies using non-curcuminoid

extracts of turmeric and no form of controls.

Studies published in English were considered for inclusion in this review. No time limit was

imposed on studies for inclusion in this systematic review as traditional usage of turmeric in

medicine has not markedly changed over time.

The databases searched included CINAHL, Embase, Cochrane Central, Pubmed, Scopus,

Psychinfo and Clinicaltrials.gov. Alternate, traditional medicine and complementary medicine

31

databases including NCCAM and NICM were searched for additional studies. Locations for

the search for unpublished studies included: Mednar, Proquest theses and dissertations, Grey

Source, Index to Theses, and Trove (Theses).

Initial keywords used were:

Turmeric, curcumin, Curcuma Longa, curcuminoids, pain

2.3.2 Assessment of methodological quality

After the data sources were searched for relevant studies, papers selected for retrieval were

assessed at the study level by two independent reviewers for methodological validity. This

was done prior to inclusion in the review, using standardised critical appraisal instruments

from the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review

Instrument (JBI-MAStARI) (Appendix II).

A threshold of six ‘yes’ responses to the assessment questions was required for a study to be

included in the review. (Appendix II). Specifically, ‘Yes’ responses were required for questions

seven to ten regarding whether the groups were treated identically other than for the named

interventions; whether outcomes were measured in the same way for all groups; whether

outcomes were measured in a reliable way; and whether appropriate statistical analysis was

undertaken. Each study was then given a Global Quality Rating. Studies which blinded the

assessors and had ‘Yes’ scores ≥80% were considered to be strong quality; those that scored

60% to <80% “Yes” scores were graded as moderate and studies that scored <60% were

classed as weak quality. Any questions answered ‘NA’ (non-applicable) were discounted from

the calculation. Any disagreements that arose between the reviewers were resolved through

discussion between the two reviewers.

32

2.3.3 Data extraction

Data was extracted from papers included in the review using the standardized data extraction

tool from JBI-MAStARI (Appendix III). Data extracted included specific details about the

interventions, populations, study methods and outcomes assessed. Additional raw data

clarifying VAS start and end-points was requested from the author(s) of four included studies

through personal communication (email).

2.3.4 Data synthesis

Meta-analysis was considered for data synthesis of primary and secondary outcomes. A large

degree of heterogeneity between the study populations (including gender balance and age),

interventions (curcuminoids, curcuminoids in combination with other herbs, curcuminoids in

combination with other herbs and minerals), intervention duration, dosage and outcome

assessment tools (VAS, modified VAS, Japanese Knee OA assessment tools, WOMAC,

modified ADL scales – non-standardised) precluded any meta-analysis of included studies.

Results of all included studies were synthesised in narrative form, with the inclusion of tables to

aid in data presentation. The assessment of publication bias was considered, but too few

sufficiently homogenous studies were obtained for the creation of an informative funnel plot.

33

Chapter 3: Results

3.1 Description of studies

A total of 1879 articles were identified from searches of databases and grey literature. After exclusion

of duplicates, 1145 articles were screened for inclusion by title and abstract relevance. A further 1122

articles were then removed. Full texts of the remaining 24 publications were assessed and a further

eight articles were removed for not meeting the inclusion criteria. One study was removed for using

non-matched controls233 and another for having no controls.132 One study was removed as its study

material was a turmeric extract but contained negligible curcuminoids.137 One study was removed for

having no curcuminoids in the herbomineral mixture.234 Four studies were removed as the measured

pain was from non-musculoskeletal sources.110, 111, 235, 236

3.2 Methodological quality

A total of 16 articles were progressed to critical appraisal where a further three studies were excluded.

These studies did not achieve minimum quality threshold.134, 237, 238 Details regarding the study

selection process are presented below in Figure 1. Further detail regarding study exclusion is provided

in Appendix III. Thirteen articles were included and progressed to the data extraction stage of the

systematic review.

All included studies achieved a “Yes” for questions relating to treatment of groups, the measurement of

outcomes and statistical analysis (questions 7-10 in the JBI Randomised Controlled Trial

(RCT)/experimental study appraisal tool)

Additionally, 12 out of the 13 studies had statistically comparable baseline characteristics (Question 6)

for study groups on entry to the studies (92.30%). However, three of the thirteen studies did not blind

the assessors (question 5), and three were unclear in their reporting (Table 1).

34

35

FIGURE 1: PRISMA FLOW DIAGRAM

Flow Diagram of Selection Process : Based on Moher D, Liberati A, Tetzlaff J, Alsmann DG. The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement PLoS Med 6(6): e1000097. Doi: 10. 1371/journal.pmed1000097

Records identified through database searching

(n = 1855)

Additional records identified through other sources

(n = 24)

Records after duplicates removed

(n = 1145)

Records screened by title and abstract (n=1145)

Records excluded that did not meet pre-defined criteria

(n = 1122)

Full-text articles retrieved and assessed for eligibility

(n = 24)

Full-text articles excluded, with reasons

(n = 8)

Studies assessed for quality (n=16)

Studies included in narrative synthesis

(n=13)

Studies excluded

(n=3)

36

TABLE 1: ASSESSMENT OF METHODOLOGICAL QUALITY OF INCLUDED STUDIES

Citation Q1 Q2 Q3 Q4 Q5 Q6 Q7 Q8 Q9 Q10 Global

Quality Rating

Nakagawa et al.184

U Y U Y U Y Y Y Y Y Moderate

Chandran and Goel203

Y U Y Y N Y Y Y Y Y Moderate

Kuptniratsaikul et al.239

Y U Y Y Y Y Y Y Y Y Strong

Kuptniratsaikul et al.181.

Y Y Y U Y Y Y Y Y Y Strong

Pinsornsak and Niempoog197

U U U U Y Y Y Y Y Y Weak

Panahi.et al.180 Y Y Y Y U Y Y Y Y Y Moderate

Kizhakkedath240 Y U U Y N Y Y Y Y Y Moderate

Drobnic.et al.241 Y Y Y Y Y Y Y Y Y Y Strong

Kizhakkedath242 Y N Y U N Y Y Y Y Y Moderate

Nieman.et al.173 Y Y Y U U Y Y Y Y Y Moderate

Udani.et al.243 U Y U N/A U Y Y Y Y Y Weak

Esmaeili Vardanjani.et

al.244 Y Y Y Y Y Y Y Y Y Y

Strong

Chopra.et al.179 Y Y Y Y Y N Y Y Y Y Strong

% of total count 76.92 61.54 69.23 66.67 46.15 92.31 100.00 100.00 100.00 100.00

Legend: Y =Yes, N=No, U= Unclear; N/A= Not Applicable

37

3.3 Systematic review findings

Of the thirteen studies included in this review; three studies investigated the effects of curcumin

versus placebo180, 184, 241, four investigated curcumin versus active control (NSAIDs),181, 203, 239, 244

and six investigated presentations of curcumin-containing herbomineral mixtures versus placebo

or active controls.173, 179, 197, 240, 242, 243

All studies were randomized control trials (RCTs). Population sizes ranged from 10 participants243

to 367 participants,181 and were conducted in India,179, 203, 240, 242 Iran,110, 180, 244, Thailand181, 197,

239, USA173, 243 and Japan184. The combined population was 1101; with subtotals for curcumin

versus placebo of n=110, curcumin versus active control of n=639, and curcumin containing

complexes versus any control n=352. Additional data was requested and received from Panahi et

al.180 Further detail regarding the characteristics of included studies are provided in Appendix IV.

The findings are discussed in the three broad categories of curcuminoids versus placebo,

curcuminoids versus active control(s), and curcuminoid-containing herbomineral mixtures versus

placebo or active controls. Each category of discussion presents sub-heading findings for pain,

function and adverse effects.

3.3.1 Curcuminoids vs placebo

Three studies180, 184, 241 that compared the effects of curcuminoids with placebo were included in

this review and are summarised in Table 2. Panahi et al180 and Nakagawa et al184 examined the

effects of curcuminoids on knee osteoarthritis (OA) pain; while Drobnic et al241 examined the

effects of curcuminoids on the pain of delayed onset muscle soreness.

Panahi et al180 evaluated the clinical efficacy of curcuminoids (1500mg/day, prepared with 5mg

bioprene to enhance bioavailability) as measured by changes in VAS and WOMAC in a double-

38

blind placebo-controlled trial where subjects (N=40) were mostly female (73.7%) Iranian knee OA

sufferers. Comparable baseline characteristics of both groups existed on entry.

Nakagawa et al184 evaluated the short-term effects of highly bioavailable curcuminoids

(presented as Theracurmin®, a registered product from Theravalues, Tokyo, Japan giving the

equivalent of 180mg/day curcumin) for treating knee OA measured by changes in VAS. They

designed a randomized double-blind placebo-controlled prospective study of 50 participants

(78.9% female; similar baseline characteristics between groups) which was carried out in Japan

over 8 weeks. Drobnic et al241 examined the effect of a commercial lecithinised curcumin

(Meriva®) at an equivalent dose of curcumin 200mg twice a day taken for four days following

induction of delayed onset muscle soreness (DOMS) in a small study of 20 healthy moderately-

active (undergoing regular aerobic exercise for at least 4 hours per week) males. Both treatment

group and placebo group commenced supplementation 24hrs prior to a downhill running test

designed to induce DOMS. Patient-reported pain intensity was recorded as an outcome, in

addition to other biochemical parameters and Magnetic Resonance Imaging (MRI) scanning

results.

39

TABLE 2: CURCUMINOIDS VS PLACEBO-CONTROLLED STUDIES

Author Sample Size

Study Design

Participants/

Condition/

Setting

Treatment Comparison Adverse Events Analysis Reported Results

DROBNIC et al.241

N=20 RCT All Healthy Males

Leg Muscles- Delayed Onset

Muscle Soreness (DOMS)

Moderate Activity at Least

4 Hrs/Week, Non=Smoking

N=10 (9 after dropout)

Phylosome (Meriva®) 1 Gram

Bd = 200mg Curcumin Bd

N= 10 Matched Placebo

No AEs Recorded Pain Intensity with 0-4 Pain Scale.

Two-Way Anova and Tukey-Kramer Test for Pair-Wise Comparisons

Total Pain in lower limbs at 48 hours No

statistically significant differences.

Curcumin group total score 23.3 +/-7.9 [17.2;29.4] versus placebo 30.6+/-

7.9[24.9;36.2] P=0.06

PANAHI et al.180

N=40

RCT Aged < 80yrs with

Degenerative Knee OA.

Tehran, Iran

VAS >= 40mm

N= 21 (5 Males) Curcuminoids 1500mg/Day

capsules for 6/52

N= 19 (4 Males)

Placebo- inert starch matched

capsules

No Serious AEs. No Withdrawal due to

AEs.

Mild Gastrointestinal Symptoms Reported

in 7 Curcuminoid group and 4 Placebo

group

Change in WOMAC, VAS, Lequesne’s Pain

Functional Index.

Comparison of Baseline Vs End-Trial Values

Used Paired Samples T-Test, Magnitude of

Changes Used Independent Samples

T-Test.

Statistically significant difference in VAS and

WOMAC global favouring the use of

curcuminoids:

Curcuminoids VAS

66.32±14.2 Baseline

36.3±17.7 Endpt

Placebo: VAS

59.05±17.3 Baseline

56.2±14.6 Endpt

40

Curcuminoids WOMAC global

42.4±18.3 Baseline

25.0±13 Endpt

Placebo WOMAC global

44.6±17.3 Baseline

40.6±12.6 Endpt

p=0.001

NAKAGAWA et al.184

N=50

RCT Aged > 40 Yrs

Knee OA

Kellgren – Lawrence Grade

II or III.

No entry level VAS stipulated

N = 25 (18 after dropouts)

5/18 males Theracurmin =

180mg Curcumin/Day for

eight weeks

N= 25 (23 after dropouts)

4/23 males Placebo for eight weeks

Subjective AEs Resulting in Dropout Curcumin 2, Placebo

1

Japanese Knee Osteoarthritis Measure (JKOM), VAS from the

JKOM with unspecified anchors or scale.

2-Sample One-Sided T-Test, Chi-Squared Test

Both treatment group and placebo group showed significant

reduction in VAS with no significant

difference between groups.

Theracumin Mean VAS 0.52 0.20, Placebo

Mean VAS 0.42 0.21

N = number of subjects, RCT = Randomised Controlled Trial, OA = Osteoarthritis, ANOVA = analysis of variance, Sig= significant, VAS = Visual Analogue Scale, Bd = twice daily, Yrs = years, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index, Endpt = endpoint

41

3.3.2 Curcuminoids versus Placebo: Measurement of Pain Outcomes

Pain was measured in Panahi et al.180 using a 0 to 10 cm VAS with the left anchor ‘0’ meaning

“no pain” and the right anchor ‘10’ meaning “worst possible pain”. Nakagawa et al.184 measured

pain with VAS but did not specify anchors or descriptors. Other measures, including use of

rescue medication and reports of joint tenderness, were also recorded. Drobnic et al.241 used a 0-

4 pain scale (with ‘0’= no pain and ‘4’ = disabling pain”) on ascending or descending stairs, with

patients indicating on a diagram the site of that pain. Drobnic et al.241 did not discuss validation of

the scale used.

Panahi et al.180 measured severity of OA pain with a 0-100mm VAS, and found that treatment

with curcuminoids was associated with statistically and clinically significantly greater reductions in

VAS scores (of over 15mm (Table 2) compared with placebo after 42 days of curcuminoids

treatment.

Nakagawa et al.184 reported improvements in VAS measures of pain for both intervention and

placebo groups compared with baseline data over the length of their study period, with the

intervention group showing a greater improvement in VAS, however this did not reach statistical

significance. The authors reported that the differences in VAS between groups became

significant if those individuals with baseline VAS scores less than 0.15, and therefore with a

lesser potential to improve, (three in each group- 16.6% in treatment group, 13.1% in placebo

group) were omitted. Raw VAS data, including scale, anchors, and specific before and after

measures were not reported by the authors in the study and could not be secured despite a

request. The longitudinal nature of the reported findings and the indeterminate nature of the VAS

measures prevented their inclusion in any meta-analysis.

42

In their small study, Drobnic et al.241 examined experimentally-induced delayed onset muscle

soreness (DOMS) and found a non-significant reduction in pain scores in the lower legs for the

treatment group compared with the placebo group. However, reduction in soreness between

groups was statistically significant for the right and left anterior thigh sites when sites were

examined individually.

Panahi et al.180 recorded the use of naproxen (a non-steroidal anti-inflammatory drug- NSAID) as

a rescue medication during the trial. A significantly larger proportion of the subjects (11 of 19=

84%) in the curcuminoids group self-reported a reduction (of unknown amount) of their naproxen

use by the end of the study compared with the placebo group (4 of 21). Over one quarter of the

curcuminoids group (5 of 19) ceased naproxen use compared with no members of the placebo

group over the course of the study.

3.3.3 Curcumin versus Placebo: Measurement of Function Outcomes

Panahi et al.180 investigated function using the WOMAC scale as a primary measure, and

Lequesne’s pain functional index (LPFI), as an additional functional measure. The data from the

reported results showed that treatment with curcuminoids was associated with significantly

greater reductions in WOMAC scores when compared with placebo after 42 days of treatment

with curcuminoids. (Table 2) The authors presented LPFI results in graphic form only and stated

that the LPFI showed significantly greater reductions when compared with placebo after 42 days

of treatment with curcuminoids. The data for Nakagawa et al.184 who used Japanese Knee

Osteoarthritis Measure (JKOM) as a primary functional outcome measure could not be

incorporated into a meta-analysis due to its longitudinal nature. That data showed improvements

in function over the treatment period for both treatment and placebo groups without a significant

difference between the groups.

43

3.3.4 Curcuminoids versus Placebo: Adverse events

Panahi et al.180 stated that no serious AEs were recorded and noted 11 cases of mild

gastrointestinal disturbance; 7 in the curcuminoid group and 4 in the placebo group (no significant

difference.) Nakagawa et al.184 reported 2 dropouts in the curcumin group (one with a feeling of

tachycardia and hypertension on day 50, and another with redness of the tongue on day 6) and

one dropout in the placebo group (from feeling unwell) on day 7. Drobnic et al.241 recorded no

AEs in their 20 subjects, with one dropout before the exercise phase due to “personal reasons”.

3.3.5 Curcuminoids versus a Positive/Active control

Four studies comparing the use of curcuminoids versus a positive/active control have been

included. Chandran and Goel203 assessed the use of curcumin, 500mg twice daily, against and in

combination with diclofenac sodium (an nsNSAID) 50mg in a study of 45 subjects with RA (7

males and 38 females) over 8 weeks (Table 3). Subjects were randomized into three treatment

groups of 15 subjects each; curcuminoids alone, curcuminoids plus diclofenac sodium and

diclofenac sodium alone. Baseline characteristics were comparable. Kuptniratsaikul et al.239

assessed the efficacy of 500mg 4 times daily curcuma domestica extracts against ibuprofen

400mg 2 times daily (an nsNSAID) in a study of 107 subjects with OA over 6 weeks.

Kuptniratsaikul et al.181 enrolled 367 OA subjects in a large multicentre study to examine the

efficacy of 1500mg/day curcuma domestica extracts versus 1200mg/day ibuprofen assessed by

pain reduction and functional improvement over 4 weeks. Esmaeili Vardanjani et al.244 compared

the effects of an applied curcumin solution and applied povidone-iodine solution in the wound

healing and pain associated with episiotomy in 120 primiparous subjects.

44

TABLE 3: CURCUMIN VS ACTIVE CONTROL STUDIES

Author Sample Size

Study Design

Participants/

Condition/

Setting

Treatment Comparison Adverse Events

(AEs)

Analysis Reported Results

CHANDRAN and GOEL203

N = 45 RCT Adult,18-65 years Active RA

Men (7) and Women (38)

N= 15 Curcumin (500mg as

BCM – 95mg) bd for 8/52

Two comparison

groups N= 15 Curcuminoids 500mg with Diclofenac (50mg) bd

group and N= 15 Diclofenac

(50 mg) bd group

3 AEs in diclofenac group, 2 in curcuminoids

group and 1 in diclofenac/curcuminoids

group. No significant differences.

Independent T test,

ANOVA, Student’s T-

test

VAS - mean baseline scores similar with % change from

baseline highest in curcuminoids

+ diclofenac (13.3%).

Curcurminoids group showed

highest reduction in pain

from baseline (59.9%). %

changes in all 3 groups

statistically significant.

KUPTNIRATSAIKUL et al.239

N=107 RCT

Adult, primary Knee OA,

Tertiary Care Medical Centre

Bangkok, Thailand VAS ≥

5

N=52 (45 after

dropouts) Curcuma extracts

500mg/4xday for 6/52

N=55 (46 after dropouts) Ibuprofen

400mg/2 x Day for 6/52

16 AEs in treatment group, 23 AEs in

comparison group. NO significant difference.

Repeated ANOVA used

to analyse main

outcomes. Differences in mean values

of pain analysed by independent

Change in pain scores baseline 6/52 assessed between two groups. No sig

differences except pain on

stairs with Curcumin group

45

T-test. Chi-Square test to

analyse adverse events

sig less pain (p=0.016)

KUPTNIRATSAIKUL et al.181

N = 367

RCT

Adult, OA Knee (Thai) aged 50 yrs + and Knee

Pain VAS ≥ 5/10

N=185 (171 after

dropouts) 1500mg curcuma

extracts/day for 4/52

N=182 (160 after dropouts)

1200 mg Ibuprofen/day

for 4/52

55 AEs in treatment group, 65 AEs in

comparison group No significant difference

Repeated- measures analysis of variance

Mean differences (95% CI) Chi

Square test, T Test

No sig difference (not-inferior)

between groups in WOMAC scores (p =

0.326, P= 0.531, P= 0.522 and P =

0.278 for WOMAC total, pain, stiffness and functional

subscales respectively

ESMAEILI VARDANJANI et

al.244 N=120 RCT

Primiparous women with no acute chronic

disease/allergy. Normal

pregnancy & delivery after 37

wks

N=60 (59 after dropout)

Curcumin solution 3x

day

N= 60 (58 after dropouts) Povidone

Iodine solution 3x day

No AEs specifically recorded, REEDA

measures recorded as outcomes

Independent 2 sample T

test. Mann – Whitney U

test.

VAS – no significant

Difference. (p= 0.027) @c 24

hrs. At 10 days vs 1st day p =

0.963 .

Legend: N = number of subjects, RCT = Randomised Controlled Trial, OA = Osteoarthritis, ANOVA = analysis of variance, Sig= significant, VAS = Visual Analogue Scale, Bd = twice daily, Yrs = years, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index, REEDA = Redness, Edema, Ecchymosis,

Discharge, Approximation

46

3.3.6 Curcumin versus a Positive/Active Control: Measurement of Pain Outcomes

Pain in the four curcuminoid versus active/positive control studies was measured using four

different scales. Chandran and Goel203 measured with 0-100mm VAS (left anchor 0 =no pain;

right anchor 100 = severe pain), Esmaeli Vardanjani et al.244 measured with 0-10cm VAS with

10mm intervals (left anchor 0 = no pain; right anchor 10 = unbearable pain), Kuptniratsaikul et

al.181 with validated Thai modified WOMAC pain measures188 (0-10cm VAS with the higher

measures representing more pain), and Kuptniratsaikul et al.239 with an 11 point numerical pain

scale from 0-10 that related to functional measures (pain on level walking and pain on stairs with

unspecified left and right anchor descriptors.)

Esmaeili Vardanjani et al.244 found no significant differences in VAS measures at 24, 48 or 240

hrs after episiotomy. Chandran and Goel203 reported that mean VAS scores for three study

groups (curcuminoids alone, curcuminoids plus diclofenac sodium and diclofenac sodium alone)

were comparable at baseline. All groups in the Chandran and Goel203 study showed a reduction

in pain as measured by a 10 cm VAS over the course of the study with the percentages of

change in VAS compared with baseline being significant at the end of study. The curcuminoids

group showed the greatest reduction in VAS from baseline (59.9%), but this reduction was not

significantly different from the reductions found for the other groups. Kuptniratsaikul et al.239

reported statistically significant improvements in all outcome measures in both groups over the

course of the study, and reported that there were no significant between-group differences, with

the exception of “pain on stairs”, which was reported as being statistically significantly less in the

curcuma domestica extract (curcuminoids) group than in the ibuprofen group. Raw numerical

pain scale data was not available for this measure; as such the clinical significance could not be

assessed. Kuptniratsaikul et al. reported that both groups showed significant improvements in

47

WOMAC pain scores over the 4-week study duration, and the non-inferiority test indicated that

curcuma domestica extracts (curcuminoids) were non-inferior to ibuprofen when the WOMAC

pain subscale was examined. Both groups improved to a similar extent and the improvement

represented a clinically significant change (defined as a change in chronic pain levels of 10-20%

by the Initiative on Measurement, Methods and Pain Assessment in Clinical Trials (IMMPACT)245)

Meta-analysis of pain results from the studies examining curcuminoids versus a positive/active

control could not be performed due to dosage differences and differences in study design.

3.3.7 Curcuminoids versus a Positive/Active Control: Measurement of Function Outcomes

To assess function Chandran and Goel203 used DAS28 (Disease Activity Scale) – a composite

index based on the assessment of 28 joints – and a Health Assessment Questionnaire (HAQ)

which included 4 categories; dressing and grooming, arising, eating, and walking. The DAS28

and HAQ both showed significant improvement over the course of study for all groups without

showing a significant difference between groups. Kuptniratsaikul et al.239 assessed function with

a timed 100m walk and timed stairs ascent and descent. No significant difference was found

between groups at the completion of the study. Kuptniratsaikul et al.181 used WOMAC functional

measures with both groups showing significant improvement in WOMAC scores over the study

duration. The results of non-inferiority testing indicated that curcuma domestica extracts

(curcuminoids) were non-inferior to ibuprofen for the WOMAC function subscale. The

heterogeneity of study designs, durations and individual outcome measurement tools precluded

meta-analysis of function results from the included curcuminoids versus positive/active control

studies.

48

3.3.8 Curcuminoids versus a Positive/Active Control: Adverse Events

Chandran and Goel203 reported that adverse events (AEs) were more common in the diclofenac

sodium group than in the other groups; three AEs were recorded in the diclofenac group (itching

around the eyes, an increase in serum glutamic pyruvic transaminase (SGPT) and SGOT,

worsening of condition, and a stated unrelated case of fever), while two AEs were reported for

the curcuminoid group (mild fever and throat infection). One case of worsening of condition was

reported for the diclofenac sodium plus curcumin group. Kuptniratsaikul et al.239 reported 16 AEs

in the curcuminoid group and 23 AEs in the ibuprofen group continuing the trend of more AEs in

the NSAIDS group. The majority of these AEs were dyspepsia, dizziness and stool consistency

differences. The rate of AEs was lower in the curcuminoid group (33.3%) than in the ibuprofen

group (44.2%), but this did not reach statistical significance. Kuptniratsaikul et al.181 similarly

found that the rate of AEs was lower in the curcuminoid group (29.7%) than in the ibuprofen

group (35.7%) with the result not reaching statistical significance. AEs were mainly abdominal

pain/distension 33/20, dyspepsia 29/21 and nausea 15/9 for ibuprofen and curcuminoid groups,

respectively. Two cases of melena were noted in the ibuprofen group, but none in the

curcuminoid group. Esmaeili Vardanjani et al.244 did not specifically report AEs in their study, but

did measure and report on REEDA parameters (redness, discharge, ecchymosis and oedema).

Those results showed a statistically significant decrease in the curcumin group (a positive finding)

compared with the active control (povidone-iodine) group.

3.3.9 Herbomineral combinations including curcuminoids versus placebo, mixed or singular active controls

Six studies examining the effects of various combinations of herbs and minerals (including

curcuminoids) on inflammation/ pain were included in this review. The heterogeneous nature of

these studies precluded their being combined in a meta-analysis, or being treated as a collective

49

for comment, as all differed in the treatment makeup, dosage, duration of application and/or

comparator. Specifically, treatment-related effects could not be confirmed as being due to

curcuminoids, as curcuminoids were presented in combination with other compounds.

Nieman et al.,173 Chopra et al.179 and Udani et al.243 compared differing herbomineral compounds

containing curcumin with placebo. Kizhakkedath242 compared a curcumin/boswellia combination

spray with an active control (diclofenac) spray. Kizhakkedath240 compared a curcumin/boswellia

compound in capsule form with celexicob (an NSAID) in capsule form while Pinsornsak and

Niepoog246 compared the effects of diclofenac (NSAID) plus curcumin with diclofenac plus

placebo. (Table 4)

50

TABLE 4 CURCUMINOID/COMPLEX MIXTURE VS PLACEBO OR ACTIVE CONTROL

Author Sample Size

Study Design

Participants/

Condition/

Setting

Treatment Comparison Adverse Events

(AEs)

Analysis Reported Results

Nieman et al.173 N = 108

RCT Charlotte NC USA, subjects 50 – 75 yrs, >

3 mths OA joint pain

knees, hips, ankles,

shoulders, hands

WOMAC 2 (+)

N=54 (50 after 4 dropouts) Instaflex for 8 weeks – 3 capsules per

day (1 TID 3 x day)

Note: instaflex = 8 substances combined including white willow bark, Boswellia serrata

extract, turmeric extract, cayenne, hyaluronic acid,

glucosamine sulphate, Methylsufonlylmethane

(MSM), ginger root concentrate

N= 54 (51 after 3

dropouts) Placebo

(magnesium sterate) for 8

weeks - 3 capsules per day (1 TID 3 x

day)

Dropouts N= 4 Instaflex, n=3 placebo

(health reasons and non-compliance)

Means+/- SD

Student T test

Generalised estimating equation, response variables

Repeated ANOVA

Total WOMAC score: A = 29.4

+/- 2.0 to 19.0+/- 1.9, placebo 30.0 +/- 2.0 to 24.6 +/-

1.0

Joint Pain severity reduced

in Instaflex compared with

placebo (8 week WOMAC, ↓37%

vs 16%, P = 0.025.

WOMAC joint stiffness ↓26%vs 18%, P = 0.035.

Joint Function index scores

↓36% vs 19%, P = 0.117 (NS)

Kizhakkedath242(Jan 2013)

N= 26 RCT Medical Centre Kochi Kerala India Subjects 19-67 yrs both

N= 13 Curcuma Longa (CL) extract in

combination with Boswellia presented in a

Spray Bottle

N= 13 Diclofenac

Spray Bottle (metal)

No adverse events related to Medication. No adverse effects in

treatment group; Comparison group one

VAS expressed in mm;

averaged and Verbal Rating

VAS- mean baseline scores

diff in scores baseline to end

of study (7 days)

51

sexes, recent soft-tissue injury last

24hrs, VAS≥ 5,

G/I event-mild aching and one burning

sensation at application site

Score expressed.

One-way ANOVA

followed by Dunnet’s Test

% pain reduction after 7 days

72.13% diclofenac

92.06% CL/Boswellia, No

stat diff B/W groups;

significant changes within

each group baseline end

Kizhakkedath240(Aug 2013)

N= 30 RCT Medical Centre in

Kochi, Kerala India Adult 18 – 65 yrs

with mod OA.

N=15 (14 after dropout) CB Formulation (CL 350mg + Boswellia

150mg =500mg) bd over 12 weeks

N=15 (14 after

dropout) Celecoxib

(100mg bd)

No adverse events. Four dropouts for “own

reasons”

Improvement in 4-point pain scale over 12

weeks. Change expressed as a

%

4-point pain scale (no, mild, moderate,

severe) Significant

change within both groups from baseline to end. NO significant

change between groups

Chopra et al.179 N= 90 RCT India (PUNE) – arthritis Camps @ centre for Rheumatic

Diseases. VAS > 4. Age limit not specified

N=45 (31 after 14 withdrawals) 10males: RA -11 (extracts of curcumin and other herbs) for 32

weeks

N=45 (31 after 14

withdrawals) 13 males;

Placebo for 32 weeks

Comprehensive reporting of AEs –no sig diff

treatment group vs placebo group. 28

patient withdrawals 14treatment/14placebo

VAS, WOMAC scores, Mean, SD/ change in efficacy over

time

ITT, with last observations

was performed

VAS & WOMAC improved

significantly better over time in curcumin and

other herbs group than

Placebo group

Note: no rescue medication

52

permitted in this study (32 weeks)

Udani et al.243 N= 10 RCT x-Over Pilot study

Healthy community

dwelling untrained

Adult subjects b/w 18 and 45 yrs 5 men and 5

women

Bounce-Back™ mixture of bromelain, proteases,

turmeric extract, phytosterols blend plus

Vit C and Japanese knotweed.

Matched Placebo capsule

No adverse events reported

Primary outcome

measures pain and

tenderness.

Pain assessed with VAS,

Tenderness with pressure

algometer/VAS

Mean differences within and

between groups were assessed inferentially at

each data collection point

using t-tests. Subjects taking

the test product experienced significant

reductions in current pain at 6 hours (p=0.038)

and 48 hours (p=0.001) with no sig diffs at other measurement

points. When VAS scores of the four questions asked were summed,

the Pre-exercise and 48 hrs post exercise totals

were significantly

53

lower in the test group.

Pinsornsak and Niempoog197

N=88 RCT Adult 38 – 80 years

Knee OA

N = 44 (37 after dropouts) Diclofenac +

Curcuminoids for 3 months

N= 44 (36 after

dropouts) Diclofenac + placebo for

three months

Renal function deterioration 2/37 and facial swelling 1/37 in

diclofenac plus placebo group, Hair loss in 1/37

in diclofenac plus curcumin group; [.

Linear model repeated measures

Descriptive T test

ANOVA

No differences in VAS (P= 0.923),

KOOS – no signif diff (p = 0.056)

N = number of subjects, RCT = Randomised Controlled Trial, OA = Osteoarthritis, ANOVA = analysis of variance, Sig= significant, VAS = Visual Analogue Scale, Bd = twice daily, Yrs = years, WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index

54

3.3.9 Herbomineral combinations including curcuminoids versus placebo, mixed or singular active controls: Measurement of Pain Outcome

Different pain scales were implemented across studies. Pain was measured with a 0-10cm VAS

by Pinsornsak and Niepoog,246 and a 0-100mm VAS by Chopra et al.,179 Kizhakkedath,242 and

Udani et al.243 Pain was measured with a 4 point verbal scale (“no”, mild”, moderate”, “severe”)

by Kizhakkedath,240 a 0-10 point VRS (no anchors defined) by Kizhakkedath,242 and with a 12-

point Likert scale (12-VS with 1= none at all and 12 = very high levels) by Nieman et al.173

Chopra et al.247 examined the effects of RA -11, a standardised multiplant Ayurvedic supplement

(Withania Somnifera, Boswellia Serrata, Zingiber Officinale and curcuma longa) versus placebo

on 90 subjects with OA. The supplement was taken twice daily for 32 weeks. No rescue

medication was allowed. The authors reported pain assessment results from a 0-100 mm

horizontal line VAS graded at 10 mm intervals anchored at 0 and 100 mm (with 0 indicating nil

pain). A statistically significant difference in improvement in the treatment group was evident

compared with the placebo group.

Kizhakkedath242 examined the effects of a curcumin/boswellia serrata combination of essential

oils topically applied as a spray thrice daily for 7 days compared with spray application of

diclofenac in the treatment of the pain of acute soft tissue injury in an open-label study. Outcome

measures were VAS and Verbal Rating Scale (VRS). In both groups, results showed a significant

difference in pain scores from baseline to day seven (curcumin/boswellia spray 92.06% reduction

versus diclofenac 72.13% reduction), with no significant difference seen between groups.

Pinsornsak and Niempoog197 evaluated the efficacy of curcumin as an adjuvant therapy for

diclofenac in primary knee OA. Overall, 44 subjects took diclofenac 75mg/day with curcumin

1000mg/day, and 44 subjects took diclofenac 75mg and a placebo for the study period of 3

months. A 0-10 cm VAS and the Knee Injury and Osteoarthritis Outcome Score (KOOS, which

55

measures 42 items on 5 separate score subscales), were evaluated monthly as outcome

measures. No significant differences were seen between groups in VAS or KOOS at the end of

the study, or at any of the time points.

Udani et al.243 examined the efficacy of a proprietary dietary supplement BounceBack™

(containing proteolytic enzymes including bromelian, curcumin, phytosterols, Vitamin C and

resveratrol) to alleviate the severity of DOMS in a small sample of 10 healthy, community-

dwelling subjects. Outcomes for pain were measured with 0-10 cm VAS and tenderness

measured with a pressure algometer (a device used to measure mechanical tissue sensitivity248,

249). This study found that at some (not all) time points in the study interval, BounceBack™

significantly lessened the complaint of pain and tenderness from DOMS compared with the

placebo.

Kizhakkedath240 evaluated the effects of a combination of 350mg curcuma longa extract and

150mg boswellia serrata extract (CB formulation) = 500mg bd against celecoxib (an NSAID)

100mg twice daily over 12 weeks in a small study of 28 OA subjects. Symptom scoring and

evaluations were carried out by an orthopaedist using questioning (4-point pain scale “no”, mild”,

moderate”, “severe”) and clinical evaluation of joint-line tenderness. The results showed

significant improvements in symptom scores within both groups over the study for pain and joint-

line tenderness. There were significant differences between groups in measures of pain and joint-

line tenderness, with the CB formulation being associated with the greater improvement in these

measures.

Nieman et al.173 examined the effects of ingestion of Instaflex™ joint supplement (a cocktail of

seven different components that included curcumin, boswellia serrata, white willow bark extract

and four others) versus placebo, over 8 weeks in a 50-75 years population. Primary outcome

56

measures obtained pre-and post-study were joint-pain severity, stiffness and function (WOMAC).

Joint pain symptom severity was measured with a 12-point Likert visual scale (12-VS). Results

obtained showed a statistically significant reduction in joint pain severity in the Instaflex™ group

compared with the placebo group commencing after 4 weeks of the study.

3.3.10 Herbomineral combinations including curcuminoids versus placebo, mixed or singular active controls: Measurement of Function Outcome

Nieman et al.173 measured function with WOMAC measures, which include measures of stiffness

and joint function that showed no significant differences over their study. Udani et al.243 measured

function with flexion/extension ROM measures. These measures showed no significant difference

over their study, with the exception of a single time-point measure (6 hrs post exercise) on the

right leg only, which significantly favoured the test product. Chopra et al.179 used WOMAC to

assess functional efficacy. Results showed a significant difference in improvement of WOMAC in

the treatment group vs placebo group. Kizhakkedath (Aug 2013)240 measured function with

walking distance and ROM. Walking distance and ROM increased significantly for both groups

with no significant difference between groups. The author drew the conclusion that the CB

formulation was as efficacious as celoxicoxib (NSAID) in improving ROM and distance walked.

Pinsornsak and Niepoog246 measured function using the KOOS, which was used by the authors

as a validated extension of the WOMAC. They found no statistically significant difference

between groups in KOOS score.

3.3.11 Herbomineral combinations including curcuminoids versus placebo, mixed or singular active controls: Adverse events

Udani et al.243 and Kizhakkedath (Aug 2013)240 reported that there were no AEs in their studies.

Kizhakkedath (Jan 2013)242 reported no AEs in the curcuminoid/boswellia group and 2 events in

the diclofenac group (one mild GI disturbance, and one redness at the application site). Chopra

57

et al.179 reported a total of 28 withdrawals in their study; 14 from the treatment group and 14 from

the placebo group; however, they stated that no withdrawals in their study were due to drug

toxicity. Chopra et al.179 reported two deaths in the treatment group (myocardial infarct and

cerebral haemorrhage) which were ascribed to pre-existing known medical conditions. Nieman et

al.173 reported a total of seven dropouts in their study (four in the curcuminoid-containing-cocktail

group and three in the placebo group), not related to study medication. No other AEs were

recorded in the study. Pinsornsak and Niepoog246 reported two cases of renal function

deterioration and one case of facial swelling in the control group (diclofenac plus placebo),

against one case of hair loss in the diclofenac plus curcuminoid group.

58

Chapter 4: Discussion and Conclusions

4.1 Introduction

The use of curcuminoids for the relief of pain and inflammation has a long history in traditional

medicine across SE Asia and the subcontinent. The support for this traditional use is found

primarily in anecdote, ritual and folklore.24 This thesis examined available evidence in studies

aiming to test the effectiveness of curcuminoids in experimental and clinical musculoskeletal pain

states. The systematic review was successful in identifying 13 studies of sufficient quality to

assist in answering this question of effect.

4.1.2 Structure of the discussion

This discussion firstly examines the influences from the systematic review on the systematic

review findings. Heterogeneity of the included studies is noted in this part with a brief elaboration

on the risks of biases in the included studies.

The findings are then discussed with respect to effects of curcuminoids in acute pain states. The

discussion then comments on effects of curcuminoids in chronic pain states, acknowledging that

all included studies had short durations.

Size of dose and effect of curcuminoids on pain is next discussed with special comment on

adjuvants. Following dose and effect, is an examination of the issue of statistical significance

versus clinical significance in the measurement of pain and function.

The body of the discussion concludes with comment on the safety of curcuminoids from a wider

literature focus narrowing to the specific findings of the systematic review.

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4.2 Heterogeneity of Included Studies

4.2.1 Characteristic Variation

Studies included in the systematic review fulfilled predetermined criteria and aimed to examine

(as a primary or secondary outcome) the effects of curcuminoids on musculoskeletal pain. As it

was not predetermined that the studies included should be homogenous in all characteristics, this

resulted in considerable heterogeneity being seen in the five major characteristics of the included

studies; namely site and structure affected by musculoskeletal pain, duration of intervention, dose

and dose frequency, comparator, and rigour of recording. These characteristics are discussed

below in greater detail.

4.2.2 Site of musculoskeletal condition and heterogeneity

The site of the musculoskeletal pain condition considered in the studies included in this review

varied from osteoarthritic joints,137, 173, 179-181, 184, 197, 239, 240 and rheumatoid joints,203 to perineum

episiotomy wounds244 and acute clinical soft-tissue injury.242 This was a complication because

scales and tools of measurement used to assess pain at the different sites are often validated for

a particular joint (as illustrated by the KOOS6, 189) or validated for a particular population and joint

(as illustrated by the JKOM183). This resulted in considerable variation in methods used for

assessing outcome measures, creating the potential for varying operator and assessor biases,

which reduced the confidence with which results could be compared across studies.

4.2.3 Duration of intervention and heterogeneity

The characteristic of duration of intervention examined in the included studies varied from 4 days

to 32 weeks, with this heterogeneity limiting the ability to pool data on duration of

treatment/duration of effect seen from treatment. This issue is covered in greater detail with a

wider literature focus in section 4.8 (Dose/effect and duration of effect).

60

4.2.4 Dose/frequency or level of intervention

The characteristic of dose of intervention was heterogeneous across the studies included in this

review. The total dose of treatment curcuminoids (or curcuminoid equivalent in mixtures) given to

subjects varied considerably, with a range from 180mg/day equivalent to 2000mg daily. (Further

discussion on dose and effect can be seen in section 4.8 below). Compounding the issue of

dose-variation as a source of heterogeneity, six studies173, 179, 197, 240, 242, 243 combined other

bioactive materials with differing amounts of curcuminoids in their active treatments. In these

studies, there was variation in both the dose or fractional amount of curcuminoids and also the

types of compounds (and their dosages) that were presented with the curcuminoids. In all of

these cases, no cross-study comparisons could be made due to heterogeneity.

The assessment of the use of curcuminoids for musculoskeletal pain can be considered to still be

in its infancy, and few quality studies using human subjects have been undertaken using the

administration of curcuminoids alone as the active treatment. A total of two studies included in

this review used the same daily dose of curcuminoids. However, their results could not be directly

compared or statistically pooled as the comparators they used differed (placebo and NSAIDS)

along with other characteristics.

4.2.5 Variation of comparator or treatment

Interpretation of findings was further complicated as the comparison treatment in the studies

varied between placebo,137, 173, 179, 180, 184, 241 NSAIDS (4 studies- 2 studies with the NSAID

comparator ibuprofen,181, 239 one study diclofenac242 and one study celecoxib240), antibacterial

agent,244 or other nutraceuticals.197 This variation of comparator across the review precluded the

statistical pooling of results of the included studies as a whole or in subgroupings.

61

With respect to treatment, included in the review were four studies173, 179, 240, 242, 243 which used

curcuminoids combined with other herbs and minerals as treatments compared with some form of

active control or placebo. Four of these studies reported significant findings reporting that the

curcuminoid-containing treatment substance significantly reduced pain. No definitive conclusion

can be drawn from these studies however, as no two or more studies used the same mixture of

ingredients with comparable study structure thereby precluding meta-analysis due to

heterogeneity. Additionally, as there were mixtures of ingredients (with each individual ingredient

in the mixture having the potential to modulate pain or function), curcuminoids cannot be singled

out as the reason for the improvement in these studies in pain or function. Specifically, treatment

related effects could not be confirmed as being due to curcuminoids, as curcuminoids were

presented in combination with other compounds.

4.2.6 Differences in recording outcomes

Differences in recording and reporting the primary and secondary outcomes existed between

most of the included studies. Visual analogue scales used had varying anchor descriptors or

none stipulated, and varied as to the unit of measurement (present or absent) in the scale.

Changes in VAS over study durations were not recorded uniformly across studies with some

studies omitting full disclosure of raw figures and using line graphs alone to demonstrate

changes. This increased the potential inaccuracy of comparisons of changes in VAS values for

pain across studies. Secondary outcomes of function were generally poorly examined across

studies with variable recording of four different scales of function (WOMAC, JKOM, KOOS and

LPFI). Differing scales of measurement of function precluded pooling of function data across

studies.

62

In summary, high heterogeneity of individual characteristics of studies in the review precluded the

ability to pool data across studies. As a result, conclusions able to be drawn from the review are

limited.

4.3 Risk of bias in included studies

The critical appraisal process undertaken as part of this systematic review aimed to exclude

studies of insufficient quality. As such, studies with an unacceptably high level of potential of bias

(see section 1.12.1) were excluded. However, the included studies still had methodological

weaknesses.

Overall, the risk of selection and performance bias in the included studies was low due to

randomised allocation to treatment groups and the blinding of subjects. Furthermore, the

baseline characteristics of the different treatment groups did not significantly differ within any of

the included studies. With respect to assessor or detection bias, three studies out of the thirteen

did not blind the assessors while a further four studies were unclear in their reporting. As such,

half of the included studies were open to potential assessor bias. The consequences of assessor

bias include the possibility that by knowing the group which a participant belongs to (treatment or

comparator), conscious or unconscious changes to responses or measurements can be recorded

or influenced by the assessor.222 Responses highlighting or supporting a particular hypothesis

may be afforded more attention by the assessor than those responses opposing that hypothesis.

This creates an increased risk that any reported changes are due to knowledge of which

intervention was received, rather than the effect of the intervention itself.222 Contextually, the

overall effect of assessor bias is likely to be an increase in the possibility of an overestimation of

treatment effect. The attrition rates between groups were not significantly different in any studies,

and reasons for withdrawal or loss to follow-up were well described. Similarly, as outcomes were

63

measured using validated measures, scales and tools and methods of reporting were

transparent, the overall risk of reporting bias for the review was assessed to be low.

4.4 Curcumin or turmeric and use in acute pain states.

Four studies were included in this review which dealt with acute pain. Two of these studies

investigated experimentally induced DOMS, one investigated acute joint pain from joint sprains

and strains, and one investigated acute pain from recent episiotomy wounds. In all these studies,

pain was of recent onset, with duration measured in days and well-less than three months. Note

that pain enduring for three months or longer can be considered chronic pain.

With specific reference to the study dealing with the pain of episiotomy wound, where the use of

a Povidone-iodine solution was compared with the use of a curcuminoid solution, no significant

difference was found in pain levels between the curcuminoid group and the povidone-iodine

group in pain over the course of the study. However, the authors’ focus in this study was to

assess wound healing, with pain being a secondary measure. Pain in this study was measured at

only two time-points. The first point at 24-48 hours post-delivery, with the second ten days post-

delivery. There were no interim pain measures taken. Both groups were similarly painful at day

one with a relatively fresh wound, and similarly close-to pain-free at Day 10. It could be

concluded that both groups reporting minimal pain at day ten of the study was reflective of the

progression of the wound-healing process. The reduction of pain may have been assisted or

impaired, accelerated (or decelerated) by the use of curcuminoids but the study design in lacking

interim pain assessment points was unable to detect this data.

64

The other three studies dealing with acute pain states similarly did not generate statistically

significant findings. Subject numbers were small to very small; potentially under-powering the

studies.

In the systematic review, the lack of evidence for curcumin moderating acute pain states is due to

the paucity of studies of any quality, the small numbers of subjects in those studies and study-

design heterogeneity. As a result, the anecdotal references to curcuminoids and turmeric being

useful in pain control in acute pain states have neither been supported or disproven in this

systematic review. More substantial studies with similar study methods are required before any

conclusion can be made as to the effectiveness or efficacy of the use of curcuminoids or turmeric

in acute clinical or experimental pain states.

4.5 Curcuminoid or turmeric use in chronic pain states

Most studies included in the systematic review involved pain associated with the clinical condition

of osteoarthritis. OA is a chronic health condition and the commonest form of arthritis. OA affects

joint surfaces as well as the joint capsule and surrounding ligaments.250 It commonly results in a

low-grade ache felt in and around a joint punctuated with periodic flare-ups of inflammation and

pain. As such, the pain experienced can be of extended duration, and if that duration exceeds

three months, falls into the category of chronic pain.1, 251

The majority of the studies examining the pain of osteoarthritic joints in the systematic review did

stipulate some osteoarthritic changes be visible on radiological imaging (most commonly

Kellgren-Lawrence Gd II changes) for the individual to be included in the study. Thus, in those

individuals in those studies it can be accepted that the chronic condition of OA was present.

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However, radiological changes and the severity of such changes do not necessarily correlate with

levels of pain or pain complaints.252

The systematic review found insufficient evidence to support the use of curcuminoids in chronic

musculoskeletal pain states where the duration of pain experienced was of three months or

greater. Problematically, none of the studies examined used durations of treatment greater than

12 weeks. Additionally, none of the studies included long-term follow-up beyond the end of the

study period or beyond three months. Not only was no long-term follow up carried out, but no

studies followed up any treatment period with assessment of symptoms at time intervals when

the subjects were not ingesting either treatment or comparator. To be able to make cogent

comment on effects of a treatment on chronic conditions which include pain states, follow-up

assessments should be made at time intervals which reasonably could encompass common

periods of remission and exacerbation. In literature, such follow-up points have been set at

varying intervals, from six months253, one year,254 to 5 years67 or longer.

There is a cultural and historical use of turmeric and curcuminoids in the short term (< 12 weeks)

for the reduction of pain associated with osteoarthritic joints.33, 255 There is insufficient evidence

from the few studies as identified by the systematic review to support or dispute this practice of

short-term pain relief. Animal studies do support the use of curcuminoids for the reduction of

inflammation as measured by inflammatory markers. Human in-vitro studies show reduction of

inflammatory markers with use of curcuminoids. The inflammation associated with OA can be

linked with the appreciation of pain associated with the condition, although pain and inflammation

do not always closely align.80, 148 It would seem reasonable that further human studies may clarify

this link.

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4.6 VAS/NRS and pain assessment- general

As pain is a subjective experience, it is difficult to measure objectively. In examining levels of pain

and fluctuations in levels, meaningful, reliable, repeatable and robust measures are required.

Standardised pain questionnaires, visual analogue scales (VAS) and numerical Rating Scales

(NRS) for pain, are in widespread use and are accepted as reliable and valid.256 All studies in the

systematic review used pain questionnaires and/or VAS or NRS to measure pain and changes in

pain over the time of the studies. Several of the studies found a statistical difference in pain

measures between groups in their study and reported on these significant findings. Seven out of

thirteen studies in this review179, 184, 197, 203, 242, 244, 257 used VAS, which is a patient–reported

measure, however the specific scales used were not uniform across the studies. Some studies

used a 10cm visual analogue scale with divisions at 1cm intervals whereas some used a 100mm

scale with no divisions; with differing anchor descriptions or no anchor descriptions. Studies were

also not uniform in stating whether their VAS or NRS was administered relating to pain

experienced over the previous 24hrs or pain experienced at the time.

4.7 VAS- statistical significance versus clinical significance

When assessing levels of pain, patient-reported measures such as VASs and NRSs are by

definition applied from the point of view of each individual subject. Even though the scale of

measurement used by each subject in a particular study is the same (e.g. 10 cm VAS), the

subjective meaning of each increment or division to each individual can vary. Not all changes in

pain levels will be considered by the patient important and considerations of importance may be

related to magnitudes of change from their baseline. For example, if a subject has no pain at all

and their baseline is zero, any additional pain that is felt will be measured on the scale. To that

subject, going from nothing to something, however small an increment, may assume great

67

importance and imply tissue damage or seriousness. To another subject who is already

experiencing high levels of pain, a change from say 7 to 8 on the scale may assume a lesser

importance.

Clinical significance refers to a change in outcome measures that represents a clinically

important difference for the subject, which should be sufficient to influence a clinician to consider

a change in clinical management.258

Seven out of thirteen studies in this review179, 184, 197, 203, 242, 244, 257 used VAS to assess levels of

pain. For VAS, the Initiative on Measurement, Methods and Pain Assessment in Clinical Trials

(IMMPACT)245 identifies difficulties in determining minimal clinically important differences (MCID).

This body has tabulated provisional benchmarks which suggest that reductions in chronic pain

intensity of at least 10-20% appear to reflect a minimal clinically important difference (MCID),

while reductions of 30% or greater reflect a moderate clinically important difference. Salaffi et

al259 directly address this issue and conclude that in chronic OA states a two-point difference on a

0-10cm VAS represents a clinically-important outcome. Six studies in this review examined OA

states, thus it follows that a two-point difference in VAS in those studies could be considered to

represent a clinically-important outcome.

Only one of the two OA placebo-controlled studies (Panahi et al180) in the systematic review

demonstrated just over two-points of difference on the VAS, favouring the use of curcuminoids.

As such, their statistically significant finding also represented a clinically important difference.

The study design used by Panahi et al180 had an important point of difference which distinguished

it from the other placebo-controlled, OA study. Panahi et al180 stipulated baseline entry-point VAS

measures of ≥4 which meant that a reduction or an increase in pain levels of 2 points was

available on the scale and able to be recorded if it did occur. This reduced the potential for a

68

potentially-confounding floor effect. On the other hand, the other placebo-controlled study in the

systematic review (Nakagawa et al184) did not stipulate a baseline entry-point of any VAS value,

which resulted in some subjects entering the study with minimal levels of pain as measured on

the VAS. It can be extrapolated that by not setting a minimum-baseline VAS for entry into the

study and accepting subjects with minimal entry-levels of pain, the authors of the study may have

encountered floor effects in their VAS measurements. Nakagawa et al184 found non-significant

findings with respect to change in pain levels over their study, but did find significant changes if

they analysed their data by removing the data of those subjects which entered the study with very

small VAS levels. While not confirming the presence of significant floor effects, this finding

supports the idea that floor effects may have contributed to the authors’ non-significant findings.

4.8 Dose/effect and duration of effect

There were insufficient studies utilising similar designs included in the systematic review to

construct a meaningful dose/effect graph for curcuminoid use. However, the majority of studies

utilised a curcuminoid dosage of 1000+mg/day and related this dose to previous dose-tolerance

studies of curcumin.130, 239, 260, 261 It should be noted that although the included studies referred to

previous dose-tolerance research on curcuminoids, none referred to any previous dose/effect

studies to justify the dose used in their respective trials.

All four studies that reported statistically significant reductions in pain associated with OA137, 180,

181, 239 used oral doses of curcuminoids of 1000mg or more per day. The only study which utilised

less than 1000mg/day in examining the pain of osteoarthritis (the authors used 180mg of

Theracumin®), showed a reduction in pain that did not reach statistical significance.184 Not

reaching significance in this instance may well have been related to magnitude of dosage of

curcumin, but also could have been related to the study design. The Nagakawa et al.184 study

69

appropriately incorporated subjects who had radiographical measures of OA (Kellgren-Lawrence

II or III), but did not specify a baseline cut off for pain intensity at entry into the study (as

previously discussed above in 4.7-( VAS- statistical significance versus clinical significance). All

other studies using VAS as a measure of pain in this review,137, 180, 181, 239 stipulated that subjects

experienced a VAS pain level of 4cm or greater (a pain level close to the midpoint of the 0-10cm

VAS) on entry to the study This ensured that if there was a potential MCID to be detected (a

change of over around 18% in VAS) it could be seen, and not precluded by a floor effect.

Measures to improve bioavailability of curcuminoids such as co-administering with piperine are

carried out to make the oral use more effective.126, 257 Only one study180 included in the

systematic review co-administered curcuminoids with piperine. That study (Panahi et al.180) found

a statistically significant and clinically significant improvement over the study period of pain levels

in the curcuminoid group versus the placebo group as measured by VAS. Further studies using

piperine are needed to clarify this finding.

Duration of administration of curcuminoids varied considerably in the studies included in the

systematic review. The shortest duration of administration was 4 weeks, with the longest being

twelve weeks. The studies’ outcome measures were measured only over the duration of the

administration period and not beyond. There were no long-term follow-ups or collections of data

reported beyond the end-points of the studies. A lack of long-term follow-up means that no

comment can be made about the durability of effect seen (if any) or the lack of any durability of

effect of the administration of curcuminoids. It also means that no comment can be made from

the results around effects on chronic pain, as the length of administration and follow up never

exceeded 12 weeks in any of the studies (as discussed above in section 4.5). As such, the

findings on effect may well only be pertinent to the time in which the curcuminoids were present

70

in the participants’ systems. No reliable human studies discuss clearance times of

curcuminoids,262 while animal studies have been unable to clearly establish parameters such as

time to peak levels in the serum or half-life of curcuminoids in vivo.262

Duration of effect is also important in discussing potential or actual adverse effects and their

occurrence and relation to dose. As curcuminoids are rapidly eliminated from the system it could

be assumed that the duration of effect is transient. However, this assumption cannot be

established as fact unless long-term follow-up studies are conducted in which curcuminoids are

first administered and then withdrawn with outcomes continuing to be monitored for an extended

period of time. The studies included in this systematic review do not extend the discussion on

duration of the effects of curcuminoids as no follow-up data was collected or presented.

4.9 WOMAC and function assessment

WOMAC measures of function were examined as secondary outcomes in four included studies in

this systematic review.173, 179-181 Only one of these studies (Panahi et al.180) directly compared

curcuminoid use with placebo and showed a statistical significant change (improvement) in

function as assessed with WOMAC.

As with VAS measures, an understanding of what constitutes a clinically significant difference in

WOMAC measures needs to be examined, as small, statistically significant results can be

recorded which would have little clinical relevance to a patient.

Stratford et al263 suggest that for the pain subscale of the WOMAC, a 4-point difference (4/20) or

20% from baseline to the end of study would constitute a true change, and by extension, an

MCID. Hmamouchi et al264 suggest a 16% reduction in the total WOMAC represents the MCID in

a Moroccan OA knee population. Using these guidelines, the statistically significant WOMAC

71

measures of function changes seen in the placebo-controlled study of Panahi et al180 achieve

minimal to moderate clinical significance. As an isolated result, unable to be statistically pooled

with other findings, caution should be used in considering its relevance to clinical practice.

4.10 Safety of Curcuminoids

Use of curcuminoids in large doses (up to 8g/day), and as a daily dose for up to three months, is

considered safe in humans.261, 265, 266 Across all studies assessed in this systematic review, the

reported AEs were not significantly different in number of events or seriousness of events

comparing the placebo groups or active control groups. This finding supports these claims of

safety. Animal studies in general support these claims of safety of curcuminoids, although a study

identifies adverse effects of curcuminoids on isolated blastocysts of pregnant mice.267

Caution concerning extended use of NSAIDS9, 268 and paracetamol is recommended in literature

269, 270, with a recent review of randomised controlled trials (RCTs) of spinal and osteoarthritic pain8

commenting that patients taking paracetamol are nearly four times more likely to have abnormal

results on liver-function tests compared with those subjects taking placebo. The four studies in the

systematic review which directly compared curcuminoid use with that of nsNSAIDS showed a trend

of fewer AEs in the curcumin groups, but did not report specifically on liver-function or kidney

function tests. As a result, there can be no comment or discussion forthcoming about the relative

merits of curcuminoids versus nsNSAIDS with respect to kidney or liver function from the findings

of the systematic review.

Likewise, as no studies in the systematic review or literature search examined curcuminoid use

against paracetamol use for pain modulation, no comment can be made on the comparative effects

of paracetamol and curcuminoids on pain modulation.

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4.11 Significance of the findings

The findings of this systematic review extend the understanding around the use of curcuminoids

in the short term (< 12 weeks) for the amelioration of pain but are insufficient to make

recommendations for or against its use in musculoskeletal pain states. This systematic review

matters because it clarifies those areas around the use of curcuminoids where our knowledge is

strong. It also importantly outlines numerous areas where our knowledge is insufficient to make

evidence-based recommendations for practice pertaining to the use of curcuminoids. At present,

paracetamol6, 269 and NSAIDS250, 269, 271, 272 are commonly recommended for use as simple

analgesics for pain control in specific or non-specific acute or persistent musculoskeletal pain

states251 including pain arising from OA. Current best-practice recommendations are silent on the

use of curcuminoids in these pain states. This is probably an appropriate reflection on the current

literature where there is a lack of high level evidence to support the use of curcuminoids in

musculoskeletal pain states.

4.12 Limitations of the review

The systematic review upon which this thesis is based was limited by several internal features its

design. The scope of the review was limited by the examination of only studies available in the

English language. This potentially resulted in the exclusion of otherwise relevant studies. This

limitation may be particularly important as the characteristics of the studies which were found

suggest that the majority of research being carried out in this field was conducted in non-English

speaking countries. It can be reasonably assumed that publishing findings in English represents

a challenge to many researchers from non-English speaking background. As such, limiting by

language could have created the potential for systematic reporting bias, as researchers with

negative or non-significant results might have been less likely to invest time and effort into

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translation compared to researchers with significant positive findings. The review was further

limited by the acceptance of studies which compared the effects of combinations of potentially

bioactive ingredients including curcuminoids with placebo or other compounds. For these studies

it was impossible to determine which, if any, effects on musculoskeletal pain states could be

attributed to curcuminoids as they were not presented as isolated treatments.

With respect to pain measurement (the primary outcome) in the review, the systematic review did

stipulate types of pain measurement tools acceptable for the included studies (VAS and pain

questionnaires) but did not clearly stipulate all parameters of the presentation or use of those

tools. There are different measurement tools/scales for VAS and also different possible

baselines, entry points and cut-offs for VAS. By not stipulating these details, studies were

included in the systematic review with heterogeneous VAS anchors, descriptors and entry points

(as discussed above in section 4.6). Those differences introduced heterogeneity into the

assessment of pain levels across the review. Further heterogeneity of data was introduced by the

systematic review protocol not stipulating whether VAS should be used as a retrospective

assessment tool for pain (pain experienced over a past period) or pain being experienced at the

time of the VAS administration. As a result, VAS data gathered from studies included results

where the measurements were for pain experienced over the previous 24 hours, or pain

measured where the time point or time frame was not stipulated. These issues of heterogeneity

contributed to the preclusion of the meta-analysis of VAS pain data across studies.

With respect to the secondary outcome measured in the review (function), the systematic review

protocol discussed the use of measures of functionality including activities of daily living and

ROM. It did not stipulate any specific measurement tools to be used, and as a result the

systematic review accepted studies which used a wide range of measures of function (including

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WOMAC, JKOM, and LPFI as discussed in section 1.9) with differing presentations and usage

protocols. The disparity between function measurement tools and the accuracy of their use made

the comparisons of changes in function impossible across studies and once again precluded the

conduct of meta-analysis.

A number of external factors associated with the characteristics of the included studies further

limited the systematic review. The primary external limitation was the small number of studies

which satisfied the inclusion criteria and were of sufficient quality for inclusion. Of the thirteen

studies included, only three directly compared the use of curcuminoids with placebo in

musculoskeletal pain conditions. As discussed above, differences in study design between those

three studies (and heterogeneity of all others in the review) precluded statistical pooling of any

degree across the review as a whole or when the studies were rendered into subgroupings.

Additionally, the small number of studies meant that any assessment of publication bias would

have been inappropriate.273 The next limitation related to the sample sizes of the included

studies. Seven of the 13 included studies had small (50 or less) sample sizes. The small sample

sizes of these studies reduced their statistical power and created the potential for spurious

findings through chance. The studies in the systematic review with the largest sample sizes used

nsNSAIDS with known and accepted modulating effects on musculoskeletal pain as comparators.

This meant that any findings from those studies could only be related to the relative effect of

curcuminoids compared with nsNSAIDS on musculoskeletal pain. These findings therefore did

not assist in directly answering the question of the effects of curcuminoids on musculoskeletal

pain.

Further limitations in the review arose from a disproportionate representation of gender in the

sample subjects. Overall, the studies recruited more women which reduces the validity of

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generalising any findings from those studies to the wider population. Additionally, the fact that

most study populations were recruited from Thailand, Iran, or Southern India further limited

generalisability. Furthermore, caution on the generalisation of findings to the whole

musculoskeletal pain population is warranted as most studies primarily dealt with osteoarthritic

knee-joint pain. Those studies that evaluated OA knees did use a standardised outcome

measure (0-100mm VAS), but there was inconsistency between studies in reporting the pain as

measured by VAS being from activity or pain over the previous 24 hours, or pain being

experienced currently as discussed above in 4.6 and 4.12. Further heterogeneity was introduced

in the assessment of stage of OA experienced by the subjects. Operator assessment of the

subjects’ stage of OA was inconsistent between studies. The assessment varied from a diagnosis

made from radiographs with a standardised assessment scale (Kellgren-Lawrence grade II-III), to

clinical orthopaedic comment (mild-moderate OA). No studies commented on intra-operator

reliability with respect to the assessment of stage of OA in subjects, or with respect to any of the

assessment methods. The inconsistency of reporting of stage of OA, and the lack of comment on

intra-operator reliability raises the question of an increased potential for selection and assessor

bias in those OA studies. In those studies, there is the potential for one operator to give greater

weight or significance to a particular feature than another operator may under the same clinical

situation.

4.13 Recommendations

4.13.1 Recommendations for practice

Further research is needed before any strong recommendations for practice relating to the use or

non-use of curcuminoids in musculoskeletal pain states can be made. The small number of

studies included in the systematic review and the heterogeneity of findings from the review inform

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this comment. It should be noted that many of the difficulties seen in the systematic review in

pooling data were due to the variation in the assessment tools used and the method of their use

and the recording of data. It is recommended that when measuring pain and function researchers

and clinicians should use standardised assessment tools, exert rigour in the standard method of

use of the tools, record the method used and contemporaneously record data. It is also

recommended that researchers include appropriate follow-up intervals in their studies, particularly

if dealing with people experiencing chronic musculoskeletal pain.

4.13.2 Recommendations for primary research

Curcuminoids versus Placebo using standardised dosages

At present, despite the numbers of published studies investigating curcuminoids increasing at a

rapid rate, there are still very few high-quality studies directly comparing the use of curcuminoids

with placebo in musculoskeletal pain conditions. Those studies that exist involve small sample

sizes, less-than robust research study design and variable dosages of curcuminoids. Initially,

therefore, high quality, larger-scale studies using standardised dosages of curcuminoids are

needed to extend the findings from the few existing studies to clarify whether the use of

curcuminoids has an effect on musculoskeletal pain states.

Longer trial durations

The literature on the effect of curcuminoids on musculoskeletal pain is primarily made up of

isolated findings from a few short-term studies. As such, further high quality research using

robust research design (RCTs with larger clinical samples) is required to examine the use of

curcuminoids for longer periods. At present there are no quality primary studies which examine

curcuminoid use beyond 12 weeks in modulating musculoskeletal pain. Future research where

the study design focusses on the use of curcuminoids mid-to-long term (beyond 12 weeks), will

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facilitate insight into the effects of the use of curcuminoids on chronic musculoskeletal pain

states.

Curcuminoids versus active alternate pharmacological agents

Future primary research is recommended to be performed comparing the use of curcuminoids

with the use of active alternate pharmacologic agents (such as nsNSAIDS) in musculoskeletal

pain conditions. Two studies were included in the systematic review which did compare the use

of curcuminoids with ibuprofen. However, further studies utilising a similar study design, but with

standardised dosages of curcuminoids are recommended to replicate and clarify their findings

and give insight into the relative value of the use of curcuminoids versus the use of ibuprofen. It is

also recommended that similar primary research studies be conducted to assess comparison

effects of curcuminoids versus other active alternate pharmaceutical agents such as selective

NSAIDS (sNSAIDS) and paracetamol (acetaminophen) in various musculoskeletal pain states.

Differing population age-groups

Studies focussing on different age-group populations are needed as most existing human studies

involve older-aged subjects. A lack of studies on younger age groups bring into question whether

findings can be generalised to the wider population. Designing studies with a younger age-group

(such as 30-50 years) would assist researchers to generalise any findings to the community.

Other categories of musculoskeletal pain

Many of the present studies in the field of musculoskeletal pain and curcuminoids target OA. It is

accepted that one of the major risk factors in osteoarthritis is increasing age274, 275 and that OA is

the most common cause of musculoskeletal disability in the elderly.276 These are likely to be the

underlying reasons behind older subjects constituting the largest proportion of the subjects in OA

studies. It is recommended that studies to assess the effects of the use of curcuminoids on other

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categories of clinical musculoskeletal pain which have a wider prevalence distribution in the

population such as low back pain, or neck pain be designed. Using those categories may allow a

more comprehensive assessment of curcuminoid effects on musculoskeletal pain in younger

populations as well as adding to the field of general knowledge on the effects of the use of

curcuminoids.

Populations external to South-East Asia, Middle East and the Indian subcontinent

Most of the current human research in musculoskeletal pain and curcuminoid use is carried out in

South-East Asia, the subcontinent or the Middle East. Generalisation of findings from present

studies to the wider population would have more validity if there were more studies involving

larger representative samples from the wider world community. As such, broadening the current

scope of research with more of this research being performed outside South-East Asia and the

sub-continent is important.

Study Design investigating absorption and elimination of curcuminoids in humans

Several very important questions pertaining to the absorption of curcuminoids in vivo in humans

are yet unresolved and are barely studied. These are: the time taken to peak in the serum; whether

magnitude of individual dose bolus matters to absorption; and the time taken for curcuminoids to

be eliminated from the system. It is conceivable that a single study primary study design could be

constructed to assess all three of these questions. Until these questions are answered, any

discussions of dose and effect of curcuminoid use lack evidence.

Other remaining questions existing around absorption of curcuminoids relate to whether there is a

latency of effect or duration of effect beyond the administration period. These questions would be

best asked after further research clarifies if an effect occurs and how magnitude of effect (if any)

relates to dose required to produce a MCID in pain.

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Study Design utilising non-curcuminoid extracts of turmeric versus placebo in musculoskeletal pain states

A small number of studies exist which discuss the effects of the non-curcuminoid portion of

turmeric on inflammation and pain.39, 137, 277 More robust primary research using larger sample-

sizes is required to clarify their limited findings. Such research could specifically compare the

effects on musculoskeletal pain of the non-curcuminoid fractions of turmeric extract with placebo.

Elaboration of this primary research to directly compare the effects (if any) of the non-

curcuminoid fraction of turmeric extract with the effects of the curcuminoid portion of turmeric

extract on musculoskeletal pain would be enlightening.

4.13.3 Future secondary research

Qualitative Systematic Reviews

Current primary research shows a dearth of strong evidence for the use of curcuminoids, even

while the use of curcuminoids grows in popularity.262 This growth in popularity could be linked to

a groundswell of word-of-mouth opinion concerning the use of curcuminoids or to other unknown

factors. No qualitative reviews were found related to the use of curcuminoids in musculoskeletal

pain states in the search. Future secondary research could explore this occurrence of increasing

use of curcuminoids and give insight to the reasons behind it, utilising a qualitative systematic

review approach.

Such a qualitative review could examine “Factors affecting the choice of curcuminoids to

modulate musculoskeletal pain”. Another qualitative systematic review could explore the narrative

“The lived experience of curcuminoid or turmeric use for musculoskeletal pain” in those already

using curcuminoids for this purpose.

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Quantitative Systematic Reviews

As there is a growing field of research into neuropathic pain treatments and complementary

medicines,278 a future suggested quantitative systematic review could ask the question “what are

the effects of curcuminoids on neuropathic pain?”. Systematic reviews considering the effects of

curcuminoids on other categories of pain, such as trigeminal neuralgia or low back pain, would

also add to the body of knowledge.

Likewise, the examination of curcuminoids on post-operative wound pain has been explored in

primary research105, 244, 279, 280 but has not yet been examined in a quantitative systematic review.

As a field, wound -care with curcuminoids and turmeric has historical roots which have informed

some of the primary researchers.

Additionally, it is of note that there are authors suggesting some bioactive effects can be related

to the non-curcuminoid portion of turmeric.137, 277 Secondary research in the form of a quantitative

systematic review examining the effects of turmeric or turmeric extract not containing

curcuminoids on musculoskeletal pain is recommended. Such a quantitative systematic review

would add to the body of knowledge and assist in clarifying which component of turmeric (or

group of compounds) if any was most bioactive.

4.14 Conclusion

The systematic review synthesized preliminary data in human studies examining the use of

curcuminoids to ameliorate musculoskeletal pain. The major finding from the review was that

there is insufficient evidence to support the effectiveness of the use of curcuminoids in

musculoskeletal pain states. Interpretation of this finding needs to be considered in the context of

significant limitations imposed by the variable quality of relevant studies, small sample sizes and

the small number of relevant studies available for examination. The systematic review

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underscored the concern that the body of evidence in the use of curcuminoids for

musculoskeletal pain is still very small despite a rapidly growing interest in the wider community.

The systematic review found that in the studies examined, the frequency or severity of adverse

events relating to the use of curcuminoids was not significantly different from placebo or other

study comparators. The findings from the systematic review support the claims of safety in

literature of the short-term use of curcuminoids. The absence of long-term follow-up across all

studies means that comment on the long-term effect of and safety of the use of curcuminoids in

musculoskeletal pain requires further high-quality research.

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Appendix I: Critical Appraisal Instrument

From the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI)216

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Appendix II: Data Extraction Instrument

From the Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument (JBI-MAStARI)216

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Appendix III: Excluded studies

Studies excluded at Full-Text Stage (N= 8)

Afshariani, R., Farhadi, P., Ghaffarpasand, F., Roozbeh, J., Effectiveness of topical curcumin for

treatment of mastitis in breastfeeding women: a randomized, double-blind, placebo-controlled

clinical trial. Reason for exclusion: Non-musculoskeletal pain

Badria FA, El-Farahaty T, Shabana AA, El-Batoty MF, Hawas SA. Boswellia -- curcumin

preparation for treating knee osteoarthritis: a clinical evaluation.233 Reason for exclusion: Non-

matched controls

Di Pierro F, Rapacioli G, Di Maio EA, Appendino G, Franceschi F, Togni S. Comparative

evaluation of the pain-relieving properties of a lecithinized formulation of curcumin (Meriva®),

nimesulide, and acetaminophen.130Reason for exclusion: Non-musculoskeletal Pain

Henrotin Y, Gharbi M, Dierckxsens Y, et al. Decrease of a specific biomarker of collagen

degradation in osteoarthritis, Coll2-1, by treatment with highly bioavailable curcumin during an

exploratory clinical trial.132Reason for exclusion: No controls

Kulkarni, M. P., Shakeel, A., Shinde, B. S., Rosenbloom, R. A., Efficacy and safety of E-OA-07 in

moderate to severe symptoms of osteoarthritis: a double-blind randomized placebo-controlled

study234Reason for exclusion: No curcumin in the herbomineral mixture

Madhu K, Chanda K Saji MJ, Safety and efficacy of curcuma longa extract in the treatment of

painful knee osteoarthritis; a randomised placebo-controlled trial137Reason for exclusion:

Negligible curcuminoids in the extract

Ryan JL, Heckler CE, Ling MN, Williams JP, Pentland AP, Morrow GR. Curcumin for radiation

dermatitis: A randomized, double-blind, placebo-controlled clinical trial of 30 breast cancer

patients.112Reason for exclusion: Non-musculoskeletal Pain

Satoskar RR, Shah SJ, Shenoy SG. Evaluation of anti-inflammatory property of curcumin

(diferuloyl methane) in patients with postoperative inflammation.111.Reason for exclusion: Non-

musculoskeletal Pain

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Studies Excluded at Critical-Appraisal Stage (N= 3)

Belcaro, G., Cesarone, M. R., Dugall, M., Pellegrini, L., Ledda, A., Grossi, M. G., Togni, S.,

Appendino, G., Efficacy and safety of Meriva(R), a curcumin-phosphatidylcholine complex, during

extended administration in osteoarthritis patients134Reason for exclusion: Did not meet critical

appraisal threshold. non-random allocation to groups, free use of rescue medication over the

course of the study, 2 authors employees of Indena S.p.A (manufacturers of Meriva® -the

material under examination in the study)

Nicol LM, Rowlands DS, Fazakerly R, Kellett J. Curcumin supplementation likely attenuates

delayed onset muscle soreness (DOMS)238Reason for exclusion: Did not meet critical appraisal

threshold; due to unclear measurement of outcomes with respect to reliability and uniformity of

measurement between groups

Kulkarni, R. R., Patki, P. S., Jog, V. P., Gandage, S. G., Patwardhan, B., Treatment of

osteoarthritis with a herbomineral formulation: a double-blind, placebo-controlled, cross-over

study237Reason for exclusion: Did not meet critical appraisal threshold; due to unclear blinding

of evaluators, unclear whether data was collected in the same way for both groups through the

study- (data missing or incomplete), unclear measurement of outcomes with respect to reliability

and uniformity

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Appendix IV: Characteristics of included studies

Study Methods Participants Intervention A Intervention B Notes

Chandran, B. and Goel, A., 2012203 Randomised Controlled Trial

18-65 YRS Rheumatoid Arthritis functional class I or

II and DAS >5.1

Curcuminoids 500mg twice daily for 8 weeks

Diclofenac 50mg twice daily for 8 weeks

Curcuminoid treatment is superior in reducing DAS

scores in RA pts cf diclofenac and appears

similar in effect to diclofenac in reducing the pain of RA

over an 8-week administration period.

Chopra, A., Lavin, P., Patwardhan, B., Chitre, D., 2004179

Randomised Controlled Trial >35 yrs primary OA one or both knees with VAS pain ≥ 4

RA-11 Ayurvedic medication (combination of curcumin and other herbs for 32 weeks

Placebo for 32 weeks

The study demonstrates the potential safety and efficacy of RA-11 in the symptomatic treatment of OA knees over a 32-week period. VAS & WOMAC improved significantly better over time in curcumin and other herbs group than Placebo group

Note: no rescue medication permitted in this study (32 weeks)

Drobnic, F., Riera, J., Appendino, G., Togni, S., Franceschi, F., Valle, X., Pons, A., Tur, J., 2014241

Randomised Controlled Trial Male, non-smoking

participants with VO2 Max >=35ml/kg

Phylosome 1 g twice daily (curcuminoids 200mg bd)commencing 48hrs prior to downhill running test and continued for 24hrs after completion of test (4 days

Matching placebo Twice a Day

Study authors measured soreness from multiple sites in the legs and summed the results. The anterior thighs were the expected sites of

soreness from a bout of downhill running. Summing

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total) the anterior thigh results with results from other sites (posterior etc) diluted

results. Study had very small sample size.

Esmaeili Vardanjani, S. A., Sehati Shafai, F., Mohebi, P., Deyhimi, M., Delazar, A., Ghojazadeh, M., Malekpour, P., 2012244

Randomised Controlled Trial

Primiparous women, without acute or chronic disease or allergy, who had a healthy

pregnancy and delivery after 37 weeks

Curcuminoid solution Povidone-Iodine solution

Pain was measured at 24 hrs (no difference in groups)

and at 10 days (no difference in groups) but note both groups were

minimal pain at 10 days-( VAS 0 and 1)

Kizhakkedath, R., 2013242 Randomised Controlled Trial 19-70 years Subjects with a painful soft-tissue injury last 24 hrs VAS≥5

Essential oil containing extracts of Boswellia Serrata and Curcuma Longa applied 3xday

Diclofenac Sodium spray applied 3xday

The results support the efficacy, safety and tolerability profile of Essential oil combination formulation comparable to the commercially available Diclofenac Sodium Spray.

Kizhakkedath, R., 2013240 Randomised Controlled Trial Moderate OA Knee pts age 18-65yrs mean age 48.5 years

Curcumin/Boswellia Serrata (CB) extracts 500mg 2x Day Celecoxib 100mg 2x Day

The Curcumin/Boswellia formulation at 500 mg administered twice a day, was more successful than administering celecoxib 100 mg twice a day for symptom scoring and clinical examination. The formulation was found to be safe and no dose-related toxicity was found. Note intervention was a combination of ingredients.

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Kuptniratsaikul, V., Dajpratham, P., Taechaarpornkul, W., Buntragulpoontawee, M., Lukkanapichonchut, P., Chootip, C., Saengsuwan, J., Tantayakom, K., Laongpech, S., 2014181

Randomised Controlled Trial OA Knee subjects Knee pain >=5/10 age >=50yrs Curcuminoids 1500mg/day Ibuprofen 1200mg/day

Curcuma Domestica extracts are as effective as ibuprofen

for the treatment of OA Knee. There was a

significantly higher number of events of abdominal pain/discomfort in the

ibuprofen grp.

Kuptniratsaikul, V., Thanakhumtorn, S., Chinswangwatanakul, P., Wattanamongkonsil, L., Thamlikitkul, V., 2009239

Randomised Controlled Trial

107 adult patients with primary knee OA with pain score >=5 and at least one

of age > 50, morning stiffness > 30 mins or

crepitus.

Curcuma Domestica extracts (500mg 4xday) for 6/52

Ibuprofen (400mg 2xday) for 6/52

The study suffered from the small sample size. The

author's comments are fair.

Nakagawa, Y., Mukai, S., Yamada, S., Matsuoka, M., Tarumi, E., Hashimoto, T., Tamura, C., Imaizumi, A., Nishihira, J., Nakamura, T., 2014184

Randomised Controlled Trial

Primary medial Knee osteoarthritis patients over

40 years of age with Kellgren-Lawrence grades II

or III on radiographic classification.

Theracurmin - 180mg curcumin (six x 30mg

tablets) daily for 8 weeks. Placebo daily for 8 weeks

Knee pain VAS scores were significantly lower in the treatment group vs the

placebo group after 8 weeks only if the scores of subjects

with initial (baseline) pain scores of 0.15 or less were

excluded.

Nieman, D. C., Shanely, R. A., Luo, B., Dew, D., Meaney, M. P., Sha, W., 2013173

Randomised Controlled Trial

Self-reported knees, hip, ankles shoulder or hands pain sufferers 50-75 years of age with pain duration ≥3months of WOMAC ≥2 pain index score

Commercialised joint pain dietary supplement (Instaflex) containing white willow bark extract, glucosamine sulphate, methylsufonlylmethane (MSM) Boswellia, turmeric root extract, cayenne, ginger root concentrate and hyaluronic acid for 8 weeks.

Placebo daily for 8 weeks

Joint pain severity was significantly reduced in the treatment group vs the placebo group after 8 weeks. Note the intervention was a mixture of 8 components.

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Panahi, Y., Rahimnia, A. R., Sharafi, M., Alishiri, G., Saburi, A., Sahebkar, A., 2014180

Randomised Controlled Trial OA pts mild--> moderate < 80 years pain on VAS ≥ 4/10

Curcuminoids C3 complex 1500mg/day (+Bioprene) Matched Placebo

Curcuminoids represent an effective and safe alternative treatment for OA. Treatment

with curcuminoids was associated with greater

reductions in WOMAC, VAS and LPFI scores compared

with Placebo

Pinsornsak, P. and Niempoog, S., 2012197 Randomised Controlled Trial

Knee OA sufferers ≥ 38yrs of age with < 30 mins of morning stiffness

Diclofenac 75mg/day with curcumin 1000mg/day for three months

Diclofenac 75mg/day with Placebo for three months

No significant difference was seen in VAS between groups at the end of the study

Udani, J. K., Singh, B. B., Singh, V. J., Sandoval, E., 2009243

Randomised Controlled Trial 18-24years community dwelling males

Bounceback™ capsules (The two capsule daily serving contained 258 mg of a proteolytic enzyme blend that included bromelain as well as proteases from Aspergillus melleus and A. oryzae also 421 mg of turmeric extract (root/rhizome; standardized to 95% curcumoids),90 mg of a phytosterol blend (beta-sitosterol, campesterol and stigmasterol), 20 mg vitamin C and 6 mg Japanese knotweed extract (root; standardized to 20% resveratrol). for 30 days prior to eccentric exercise protocol test

Matching placebo for 30 days

BounceBack™ capsules were able to significantly reduce standardized measures of pain and tenderness at several post-eccentric exercise time points (but not all) in comparison to placebo. Study limited by very small sample size (10 subjects). Note BounceBack™ capsules were a diverse mixture of proteolytic enzymes and other ingredients including curcuminoids.